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  5. 阿尔茨海默病：危险因素、早期识别、诊断与防治策略综述

阿尔茨海默病：危险因素、早期识别、诊断与防治策略综述

深度研究匿名用户发表于 2025年09月16日 19:131阅读
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1. 阿尔茨海默病的危险因素分析

1.1 不可变危险因素

阿尔茨海默病（AD）的发生发展受多种因素影响，其中一些因素是不可改变的，如年龄、遗传背景和生物学性别。深入理解这些不可变危险因素的作用机制，对于识别高风险人群和制定早期干预策略至关重要。

年龄是AD最主要的不可变危险因素。随着年龄的增长，AD的发病风险显著增加。尽管AD长期被认为是衰老的必然结果，但近年来研究表明，通过管理可变风险因素，AD的发病率和患病率在西方国家呈现下降趋势，这提示AD并非完全不可预防1。然而，年龄对AD风险的影响在所有族裔、年龄段（40-90岁之间）和性别中都普遍存在2。

遗传因素在AD的发生中扮演着核心角色，其中载脂蛋白E（APOE）基因的ε4等位基因是散发性AD最强的遗传风险因子，而APOE ε2等位基因则被认为是AD的保护性因子345。具体而言，携带APOE ε4等位基因的个体患AD的风险显著升高，且其风险与ε4等位基因的拷贝数呈剂量依赖性关系——即携带的ε4等位基因数量越多，患病风险越高，发病年龄越早26。例如，在迟发性AD的家族研究中，APOE ε4纯合子的AD风险可高达90%，且平均发病年龄降至68岁6。APOE ε4主要通过驱动淀粉样蛋白病理学（如淀粉样蛋白斑块的早期和更大量沉积）、影响tau蛋白病理学、介导小胶质细胞反应以及损害血脑屏障等多种机制增加AD风险347。

性别差异也是AD风险中的一个重要不可变因素。流行病学数据显示，女性患AD的风险高于男性，这引发了对性别特异性病理机制的广泛关注891011。绝经后女性雌激素水平的降低被认为是导致其AD风险增加的潜在因素之一8121314。雌激素在脑功能中发挥关键的生理作用，对神经元健康、淀粉样前体蛋白（APP）的加工以及脑源性神经营养因子（BDNF）的调节均有重要影响81214。研究表明，雌激素水平的长期剥夺与AD的进展密切相关，特别是雌激素受体（ERα和ERβ）在AD患者海马神经元中的表达降低12。此外，早期绝经与突触完整性对AD风险的影响存在显著交互作用，即早期绝经会加剧突触功能受损与认知衰退和tau蛋白缠结之间的关联15。这些发现强调了荷尔蒙因素在女性AD病理生理学中的独特作用，为开发基于性别的精准医疗策略提供了依据101116。

1.2 可变危险因素

除了不可变的遗传和年龄因素，阿尔茨海默病（AD）的发生发展还受到一系列可变危险因素的影响，这些因素为AD的预防和干预提供了重要的切入点。流行病学研究指出，AD的病理进程可能在临床症状出现前数十年就已经开始 17，因此，针对这些可变危险因素的早期干预对于预防或延缓AD的发生具有关键意义 1718。

血管疾病是AD重要的可变危险因素。高血压、糖尿病和高胆固醇血症等血管危险因素在中年时期（65岁以前）的出现，被认为会增加晚发性AD的风险 1920。例如，高血压不仅可能通过损害脑血管内皮功能、改变脑血流量和促进血脑屏障功能障碍来直接影响脑健康，还会间接促进Aβ的沉积和tau蛋白的病理改变。糖尿病则会引起胰岛素抵抗和高血糖，导致神经炎症和氧化应激，从而加速神经退行性病变。此外，有研究表明，血管性痴呆与AD的病理生理学之间存在重叠，这进一步凸显了血管健康对预防AD的重要性 19。

头部外伤（TBI）也被确认为AD及相关痴呆（ADRD）的一个潜在危险因素 2122。一项对57项研究的荟萃分析显示，既往有TBI史的个体，后续诊断为神经和精神疾病的风险显著增加，其中AD的发生几率更高 21。即使是轻度TBI（mTBI），也与AD风险的增加相关 23。虽然具体机制仍在研究中，但TBI可能通过诱导神经炎症、Aβ积累和tau蛋白病理等方式，加速神经退行性进程 21。

慢性感染与AD的关联也日益受到关注。虽然传统观点认为大多数神经退行性疾病并非由病原体引起，但一些新兴研究表明病毒感染可能与神经退行性疾病存在关联 24。例如，肠道菌群失衡（生态失调）与神经退行性疾病之间存在强烈的关联 25。肠道-脑轴（gut-brain axis）的健康与否对维持大脑健康至关重要，肠道微生物群的组成不仅可能用于神经退行性疾病的早期诊断，甚至可能通过调节肠道-脑轴来作为治疗靶点 25。此外，其他慢性感染，如导致神经炎症和免疫应答失调的感染，也可能间接增加AD风险。例如，SARS-CoV-2感染被发现能影响与神经退行性疾病发病机制相关的神经元群，引发对长期神经系统影响的担忧 26。

环境暴露，特别是长期接触某些环境污染物，被认为是AD风险增加的因素之一 272829。重金属（如铅、汞）、农药、多氯联苯以及空气污染物等都已被证明具有神经毒性 29。这些毒素可能通过多种机制促进AD病理，包括诱导Aβ斑块和tau蛋白缠结的沉积、促进细胞凋亡、引发炎症反应和氧化损伤等 2829。

生活方式在上述可变危险因素中扮演着中介作用。低体力活动和肥胖被广泛认为是AD的独立危险因素 2030。缺乏身体活动不仅增加肥胖和血管疾病的风险，也直接影响脑部的血液供应和神经营养因子的分泌 3132。中年的高BMI（体重指数）和晚年的体重减轻均与AD风险增加有关 20。积极的生活方式，如保持身体活跃，可以帮助维持认知功能，并通过多种保护机制，如调节Aβ代谢、减少炎症、增加神经营养因子合成和改善脑血流，来预防和治疗AD 3132。饮食模式（如不健康的饮食习惯）也与AD风险密切相关，例如，富含抗氧化剂的均衡饮食对大脑健康、血糖控制、体重管理和心血管健康至关重要 32。综合来看，这些可变因素的有效管理和健康生活方式的采纳，是实现AD早期预防和延缓疾病进展的关键策略 333435。

1.3 多因素交互作用

阿尔茨海默病（AD）的病因复杂，其发病并非单一危险因素作用的结果，而是遗传易感性与环境/行为因素之间复杂的协同作用。这种多因素交互作用可以显著改变个体患AD的风险，并影响疾病的发生年龄和进展速度。

其中，APOE ε4基因型与多种环境及生活方式因素的协同效应得到了广泛关注。APOE ε4是AD最主要的遗传风险因素，但其致病作用常与外部环境因素相结合而增强。例如，APOE ε4携带者若同时存在高血压，其AD风险会进一步升高36。研究发现，高血压、糖尿病、肥胖以及抑郁症等疾病，尤其是当它们在62岁之前发生时，对AD风险的影响可能比单独的APOE ε4基因型更大36。例如，在62岁之前诊断为高血压或糖尿病的个体，其患AD的风险高于单独携带APOE ε4的个体36。肥胖在62岁前发生可使AD风险增加54%，若在62-72岁之间，风险几乎增加三倍36。这些发现表明，遗传背景与生活方式或慢性疾病的叠加效应，对AD的发病具有关键的“临界点”影响。

除了心血管危险因素，其他基因与环境/行为因素的交互作用也已被证实。例如，APOE ε4与家族史（Family History, FH）之间存在显著的协同作用。在认知正常的中老年人中，同时携带APOE ε4等位基因且有迟发性AD家族史的个体，其脑内的淀粉样蛋白（Aβ）沉积和脑葡萄糖代谢异常更为显著37。这提示，家族史中可能包含了一些未被明确的遗传或环境风险因素，它们与APOE ε4共同作用，加速了AD相关的脑部病理改变37。

此外，APOE ε4与其他基因的交互作用也值得关注。例如，在非洲裔人群中，APOE ε4等位基因与ABCA7基因的移码缺失共同作用，可以显著降低AD的发病年龄38。ABCA7基因的缺失会使APOE ε3/ε4携带者的生存期显著缩短，提示这两种基因之间存在协同效应38。同样，胆固醇代谢相关的HMGCR和ABCA1基因多态性也可能与APOE ε4相互作用，共同调节AD风险39。

免疫系统在AD病理中的作用也受到APOE ε4的影响。APOE ε4携带者在神经退行性疾病中普遍表现出一种促炎症的免疫特征，这种特征在脑脊液、血浆和脑组织中均可观察到，且与神经退行性病理（如Aβ和tau蛋白）的程度无关40。这种系统性的免疫易感性提示，APOE ε4可能通过调节免疫反应与环境因素（如感染、炎症）相互作用，从而驱动神经退行性过程40。

这些多因素交互作用的证据，强调了AD预防和治疗策略需要综合考虑遗传背景和个体化的环境暴露及生活方式，而非仅仅关注单一风险因素。理解这些复杂的相互作用，有助于开发更精准的风险评估模型和更有效的干预措施。

2. 阿尔茨海默病的早期症状识别

阿尔茨海默病（AD）的早期识别对于及时干预和延缓疾病进展至关重要。与正常衰老引起的轻微认知功能下降不同，早期AD的症状往往更为显著，并对日常生活功能产生影响。识别这些早期症状，特别是认知功能和非认知行为的改变，是区分正常衰老与病理状态的关键。

2.1 认知功能异常

AD早期最显著且核心的临床表现是认知功能异常，尤其在记忆、执行功能和语言方面。这些异常通常是渐进性的，并随着疾病的进展而恶化。

记忆障碍：记忆力下降是AD最典型的早期症状，其中情景记忆减退尤为突出 41。患者可能难以记住最近发生的事情、新学到的信息或重要的约会。例如，他们可能反复询问相同的问题，忘记将物品放在哪里，或者忘记最近的对话内容。这种记忆障碍与正常衰老时偶尔出现的“健忘”（如暂时性地忘记某人的名字或词语，但在提示后能回忆起来）有本质区别。在正常衰老中，虽然信息提取速度可能减慢，但通常能有效编码和储存新信息。AD是一种进行性神经退行性疾病，以认知能力下降、记忆丧失和日常功能受损为特征 42。这种记忆损害不仅限于事件记忆，还可能累及语义记忆和程序记忆。参考文献11指出，虽然情景记忆下降是AD的认知标志，但关于APOE ε4等位基因对AD患者情景记忆下降影响的研究存在争议，且未提及语义记忆和程序记忆的具体情况。

执行功能下降：执行功能是指个体进行目标导向行为、解决问题、计划和组织活动的能力。AD早期患者常表现出执行功能障碍，例如决策困难、计划和组织日常任务的能力下降 41。他们可能难以完成多步骤的任务，如烹饪复杂的菜肴、管理财务或组织旅行计划。患者在处理新情况或应对突发事件时可能会感到困惑和无所适从。此外，选择性注意力和抑制干扰信息的能力也会受损，这使得他们在需要集中注意力的环境中表现不佳 41。这些执行功能障碍对患者的独立生活能力产生显著影响，是区分正常衰老与早期AD的重要指标。

语言障碍：AD早期患者也常出现语言障碍，主要表现为词汇量减少、找词困难（命名障碍）和言语流畅性下降 4344。患者在交流时可能难以找到恰当的词语来表达自己的想法，导致言语内容空洞、犹豫不决或使用通用词语（如“那个东西”）。他们可能会出现命名错误、理解复杂句子困难或难以跟上对话的节奏 45。与正常衰老中偶尔出现的“舌尖现象”（即暂时性地想不起某个词，但最终能回忆起来）不同，AD患者的找词困难更为持久且普遍，即使给予提示也难以回忆 43。随着疾病的进展，语言障碍会进一步恶化，影响患者的日常沟通能力 46。

值得注意的是，这些认知功能异常在早期AD中可能表现为轻度认知障碍（MCI），这是一种介于正常认知衰老与痴呆之间的过渡阶段 47。MCI患者的认知功能损害尚未严重到影响其独立生活能力，但其认知测试表现已低于同年龄、同教育背景的正常人群。每年约有8%至15%的MCI患者会进展为痴呆，其中大部分是AD 47。因此，对MCI阶段的准确识别和密切监测对于早期干预至关重要。

2.2 非认知症状

除了认知功能异常，阿尔茨海默病（AD）的早期阶段还常伴随一系列非认知症状，这些症状往往比明显的记忆力下降更早出现，被称为行为和精神症状（Behavioral and Psychological Symptoms, BPS）。识别这些非认知症状对于早期预警和干预具有重要意义 4849。

行为和精神症状：
在AD的早期阶段，患者可能出现冷漠、抑郁、焦虑和激越等行为和精神症状 49。这些症状通常与AD病理进程并行发展，可能作为神经退行性变的早期信号 49。

  • 冷漠：表现为兴趣减退、缺乏主动性、情感平淡。患者可能不再积极参与曾经喜欢的活动，对周围环境漠不关心，甚至对个人卫生也不再重视。冷漠在AD早期阶段很常见，并且会对患者及其照护者的生活质量产生显著影响 4950。
  • 抑郁：早期AD患者常出现情绪低落、失眠、食欲不振、缺乏精力等抑郁症状。这些症状可能被误诊为单纯的抑郁症，但其内在机制与AD的神经病理变化密切相关 4950。
  • 激越：表现为烦躁、易怒、坐立不安、攻击性行为。激越的发生可能与脑内炎症反应以及特定神经递质系统的失衡有关 50。

感官异常：
感官功能障碍在AD患者中普遍存在，并且常常在认知症状出现之前就已经出现 5152。

  • 嗅觉辨别能力下降（嗅觉功能障碍）：嗅觉丧失或辨别能力下降是AD最早期的非认知症状之一，甚至可能比认知症状早数年出现 515354。有研究表明，嗅觉障碍的模式和类型可能成为AD早期诊断的有用工具 55。嗅觉功能障碍与大脑病理标志物（如淀粉样蛋白和tau蛋白）的积累密切相关 5156。例如，对常染色体显性AD（ADAD）突变携带者的研究发现，较差的嗅觉识别表现与年龄增长、MMSE评分降低以及大脑中淀粉样β和tau蛋白病理负荷增加有关 56。此外，AD患者嗅觉功能受损可能与蓝斑核（Locus Coeruleus, LC）去甲肾上腺素能轴突的早期损失有关，这种损失甚至发生在淀粉样斑块出现之前 57。
  • 其他感官异常：除了嗅觉，味觉和听力受损也与AD密切相关 5152。例如，听力障碍被显著地与AD相关联，尽管其对AD进展的因果影响尚不明确 51。视觉和触觉缺陷，包括视网膜变薄和触觉感知变化，也被认为是AD进展的指标 51。

社会认知障碍：
社会认知是指个体理解、处理和运用社会信息的能力，包括识别他人情绪、理解社会情境以及表现出适当的社会行为。AD早期患者可能出现共情能力减退和社会退缩。

  • 共情能力减退：患者可能难以理解他人的情感和意图，对他人痛苦或需求缺乏反应，导致人际关系紧张。这种社会认知障碍可能与AD早期大脑中枢神经回路的改变，特别是室旁（PV）中间神经元的功能障碍有关 5859。
  • 社会退缩：患者可能避免社交活动，对与人交流失去兴趣，倾向于独处。这不仅是冷漠的表现，也反映了其社会认知能力的下降 59。

情感干预对冷漠症状的改善案例：
针对早期AD的非认知症状，特别是冷漠，情感干预等非药物疗法显示出潜力。虽然具体的案例在提供的文献中未详细说明，但研究表明，早期识别和干预这些行为和精神症状，可能有助于改善患者的生活质量并延缓疾病进展。例如，有研究提出催产素（Oxytocin, OT）作为一种潜在的治疗剂，可以通过调节PV中间神经元功能来改善AD早期的社会认知缺陷 58。此外，理解个性结构及其在AD早期阶段的变化，对于识别行为和精神症状（如冷漠、抑郁、焦虑、激越）作为神经退行性变的早期预警信号至关重要 4960。针对这些症状的个性化管理和干预，将有助于提升患者及其照护者的福祉。

2.3 神经病理关联

阿尔茨海默病（AD）的早期症状，无论是认知功能异常还是非认知症状，都与大脑中复杂的神经病理变化密切相关。理解这些症状与潜在病理学之间的对应关系，对于早期诊断和开发靶向治疗至关重要。AD的两个主要病理学特征是细胞外β-淀粉样蛋白（Aβ）斑块的沉积和细胞内神经原纤维缠结（NFTs）的形成，后者由异常磷酸化的tau蛋白组成 6162。此外，神经炎症，尤其是小胶质细胞的激活，也被认为是AD发病机制中的关键因素 6364。

β-淀粉样蛋白沉积与早期症状：
Aβ肽的过度产生或清除受损导致其在大脑组织中积累，形成老年斑和神经炎斑块 6165。这种积累可以发生在临床症状出现前数十年 616667。早期证据表明，Aβ的积累与AD的早期认知障碍密切相关。例如，Aβ斑块的早期沉积可能导致突触功能障碍和神经元损伤，这进而影响记忆形成和巩固，解释了早期情景记忆减退的现象。脑脊液（CSF）中Aβ42水平的降低以及淀粉样蛋白PET成像显示的Aβ沉积，是AD早期阶段的重要生物标志物，甚至在轻度认知障碍（MCI）阶段就能检测到 6168。有研究表明，焦虑与AD之间存在紧密的生物学联系，并且这种联系在早期阶段就开始，影响功能衰退。Aβ斑块的累积与焦虑症状强度之间存在关联，这提示Aβ病理可能在AD早期通过某种机制引发或加剧焦虑 69。此外，淀粉样蛋白的积累也被认为是引起脑淀粉样血管病（CAA）的原因，可能通过影响脑血管功能进一步加剧认知障碍 70。

Tau蛋白异常磷酸化与早期症状：
tau蛋白的异常磷酸化导致其从微管上解离并聚集形成神经原纤维缠结（NFTs） 6171。tau病理与神经退行性变和临床症状的出现时空上高度相关 72。相比Aβ病理，tau病理与认知功能障碍的严重程度有更好的关联性 71。早期tau蛋白缠结通常首先出现在内嗅皮层和海马区，这些区域与情景记忆的形成密切相关，这解释了早期记忆减退与tau病理的关联。随着疾病的进展，tau病理会扩散到大脑的其他区域，导致执行功能、语言和视觉空间能力等更广泛的认知功能障碍 73。新的tau-PET示踪剂能够检测到最早疾病阶段内侧颞叶区域的tau病理，以及更准确地反映tau缠结负荷的新型磷酸化tau（p-tau）生物标志物（如p-tau181、p-tau217和p-tau231）在CSF和血液中的应用，为早期诊断和疾病进展监测提供了有力工具 72。焦虑症状也已被证实与早期Braak分期的tau病理相关 69。

小胶质细胞激活与早期症状：
小胶质细胞作为大脑的常驻免疫细胞，在AD病理生理学中发挥着双重作用。在疾病早期，小胶质细胞可能通过吞噬Aβ斑块来发挥保护作用，但慢性激活的小胶质细胞会释放促炎细胞因子，导致神经炎症和神经元损伤 6364。这种神经炎症反应被认为是AD发病机制中的一个关键因素 62。新近的研究发现，小胶质细胞活性状态的生物标志物面板（如FABP3, GDI1, MDH1）能够区分AD患者与对照组，并且这些标志物在淀粉样蛋白阳性的轻度认知障碍（MCI）病例中显著升高，这表明它们与淀粉样蛋白播种的早期免疫反应相关 68。小胶质细胞功能障碍还可能通过影响突触可塑性和神经发生，进一步加剧认知功能障碍 63。

社会认知减退与PV中间神经元功能失调的联系：
社会认知障碍，如共情能力减退，是AD早期可观察到的症状之一 58。研究指出，这些早期变化与室旁（Parvalbumin, PV）中间神经元的功能障碍密切相关 58。PV中间神经元是抑制性神经元，在调节大脑皮层兴奋/抑制平衡、节律活动以及高级认知功能（包括社会认知和记忆）中发挥关键作用。AD早期，PV中间神经元可能会受到Aβ和tau病理的损伤，导致其功能失调。这种功能失调可能导致特定脑区（如前额叶皮层和社会认知相关网络）的神经回路异常，进而表现为社会认知能力的下降。催产素（Oxytocin, OT）作为一种潜在的PV中间神经元调节剂，被认为有望成为改善AD早期社会认知缺陷的治疗策略 58。

综上所述，AD的早期症状是复杂的病理过程在临床层面的体现。Aβ的沉积、tau蛋白的异常磷酸化以及小胶质细胞的激活共同构成了疾病的核心病理学，并以不同的方式影响认知和非认知功能。PV中间神经元功能失调与社会认知障碍的关联，更是揭示了AD早期病理机制的精细复杂性，为我们提供了更全面的疾病理解和潜在的早期干预靶点。

3. 阿尔茨海默病的诊断技术与挑战

阿尔茨海默病（AD）的诊断是一个复杂且不断发展的领域，旨在尽可能早期、准确地识别疾病，以便及时进行干预。目前，AD的诊断主要依赖于临床评估、神经心理学测试、生物标志物检测以及新兴的影像学和AI技术。然而，这些方法在实际应用中仍面临诸多挑战。

3.1 临床评估与量表应用

临床评估是AD诊断的基础，涉及详细的病史采集（包括患者和家属提供的信息）、神经系统检查以及认知功能的评估。为了标准化和量化认知功能障碍的程度，医生会使用各种神经心理学量表。这些量表能够帮助区分正常衰老、轻度认知障碍（MCI）和阿尔茨海默病痴呆阶段，并追踪疾病进展。

认知量表应用：

  • 整合性阿尔茨海默病评定量表（iADRS）：iADRS是一个综合性量表，用于评估AD患者的认知和功能障碍，评分范围为0到144，分数越低表示功能受损越严重。在临床试验中，iADRS被广泛用作主要结局指标，用于评估疾病修饰疗法的疗效。例如，Donanemab的III期临床试验结果显示，在低/中度tau蛋白病理的早期症状性AD患者中，donanemab组在76周时的iADRS评分变化为-6.02，而安慰剂组为-9.27，差异为3.25分，表明其能显著减缓疾病进展 74。对于轻度AD患者，iADRS评分-9分的变化被认为是具有临床意义的最小改变（MCID）75。这强调了iADRS在衡量治疗效果和疾病进展方面的敏感性。
  • 临床痴呆评定量表-总和盒（CDR-SB）：CDR-SB是一个评估认知和功能障碍严重程度的量表，评分范围为0到18，分数越高表示功能受损越严重。与iADRS类似，CDR-SB也被用于评估治疗效果。Donanemab的TRAILBLAZER-ALZ 2试验结果显示，在低/中度tau蛋白病理的患者中，donanemab组的CDR-SB评分变化为1.20，安慰剂组为1.88，差异为-0.67，同样显示出治疗组疾病进展的减缓 74。对于轻度认知障碍（MCI）患者，CDR-SB评分+1分的变化被认为是临床有意义的，而对于轻度AD患者，+2分的变化则被视为有意义的 75。CDR-SB的敏感性使其成为衡量早期AD进展的重要工具 76。
  • 阿尔茨海默病评估量表-认知子量表（ADAS-Cog）：ADAS-Cog是专门用于评估AD患者认知和非认知行为功能障碍严重程度的量表，其由21个项目构成，具有良好的信度和效度 77。对于MCI患者，ADAS-Cog评分+2至+3分的变化被认为是临床有意义的，而对于轻度AD患者，+3分的变化则被视为有意义的 75。
  • 简易精神状态检查（MMSE）：MMSE是最常用且广泛接受的认知筛查工具之一，用于快速评估认知功能。然而，MMSE在诊断轻度认知障碍方面的敏感性受到教育水平、年龄和国籍等因素的影响，因此其在早期诊断中的局限性也日益凸显 78。尽管如此，MMSE评分的变化仍然具有一定的临床意义，例如MCI患者-1到-2分的变化，轻度AD患者-2分的变化，以及中度至重度AD患者-1.4到-3分的变化都被认为是临床有意义的 75。

神经心理学测试：
除了上述量表，一系列更细致的神经心理学测试被用于评估特定的认知领域，以区分AD与其他神经系统疾病。

  • 言语流畅性评估：言语流畅性测试，如范畴流畅性（例如，在给定时间内说出尽可能多的动物名称）和字母流畅性（例如，说出以字母F开头的词），在区分AD和其他认知障碍方面具有较高价值 79。AD患者通常在范畴流畅性方面表现出比字母流畅性更显著的下降，尤其是在疾病的早期阶段 79。
  • 记忆测试：延迟情景记忆（如Rey听觉语言学习测试-延迟识别）被认为是区分AD与晚发性抑郁症的重要指标 80。
  • 命名和视空间能力测试：波士顿命名测试（Boston Naming Test）和痴呆评定量表（Dementia Rating Scale）中的构建和概念化子量表，对于鉴别AD和晚发性抑郁症也具有较高的特异性 80。

早期诊断的综合判断：
强调早期诊断需结合症状持续时间与功能影响的综合判断。仅凭量表分数或神经心理学测试结果不足以确诊AD。医生需要综合考虑患者认知症状的出现时间、进展模式，以及这些症状对患者日常生活功能（如穿衣、做饭、财务管理等）的影响程度。认知障碍持续时间、进展速度及其对日常生活活动能力（Instrumental Activities of Daily Living, IADL）和基本日常生活活动能力（Basic Activities of Daily Living, BADL）的影响，是评估疾病严重程度和诊断类型的重要依据。例如，功能活动问卷（FAQ）在评估AD临床进展方面表现出较高的敏感性，甚至优于纯认知领域的测量 76。在评估患者时，医护人员还应排除其他可逆性认知障碍的原因，如维生素缺乏、甲状腺功能减退或药物副作用等。因此，AD的早期诊断是一个多学科、多维度、需要动态评估的过程，强调将标准化量表与个体化临床判断相结合。

3.2 生物标志物检测

随着医学技术的进步，生物标志物在阿尔茨海默病（AD）的诊断中扮演着越来越重要的角色，尤其是在疾病的早期识别和区分不同病理类型方面。生物标志物可以反映疾病的潜在病理过程，即使在临床症状出现之前，也能提供疾病存在的证据 81。目前主要关注的生物标志物包括脑脊液（CSF）标志物、血液标志物以及影像学标志物（PET）。

脑脊液（CSF）生物标志物：
CSF标志物是目前公认的、诊断AD的核心生物标志物，具有较高的敏感性和特异性 8283。主要包括：

  • 淀粉样蛋白-β42 (Aβ42)：AD患者脑内Aβ42沉积形成斑块，导致CSF中可溶性Aβ42水平下降。因此，CSF Aβ42水平降低是AD淀粉样病理学的一个关键指标 8183。Aβ42/Aβ40比值被认为可以提高检测淀粉样蛋白病理学的准确性 83。
  • 总tau蛋白 (T-tau)：T-tau反映神经元损伤和变性程度。AD患者脑内神经元损伤导致T-tau释放到CSF中，因此CSF T-tau水平升高 8283。
  • 磷酸化tau蛋白 (P-tau)：P-tau特指在AD中异常磷酸化的tau蛋白，主要反映AD的神经纤维缠结病理。CSF P-tau水平升高与AD的tau病理学直接相关 818283。

这三种核心CSF标志物（Aβ42、T-tau和P-tau）能够有效区分AD患者与健康对照组，并能区分AD引起的轻度认知障碍（MCI）与稳定型MCI 82。它们已纳入AD的研究诊断标准，并在临床试验中用于识别具有核心AD神经病理特征的患者 83。然而，CSF取样具有侵入性，限制了其在临床实践中的广泛应用 84。

血液生物标志物：
血液生物标志物因其微创性和易于获取的特点，成为AD诊断研究的热点方向，有望实现早期、便捷的疾病筛查和监测 848586。

  • 磷酸化tau蛋白 (p-tau)：血浆中的磷酸化tau蛋白，特别是p-tau181、p-tau217和p-tau231，已被证明是AD病理学的高度特异性指标 8788。它们与脑内淀粉样蛋白沉积和tau病理学具有良好的相关性 89。研究显示，血浆p-tau217在区分AD和其他神经退行性疾病方面表现出优异的诊断性能，甚至优于p-tau181 87。它在诊断AD方面的准确性可与CSF和PET标志物媲美，并且能够预测淀粉样蛋白PET的阳性结果 8890。最新的研究表明，p-tau217与非p-tau217的比值（p-tau217%）结合Aβ42:Aβ40比值（构成淀粉样蛋白概率评分2, APS2）在初级和二级医疗机构中对AD具有高诊断准确性（88%-92%） 91。
  • 淀粉样蛋白-β (Aβ)：血浆Aβ42/Aβ40比值也用于指示脑内淀粉样蛋白沉积 90。然而，血浆Aβ标志物的诊断准确性通常低于p-tau标志物 82。
  • 神经丝轻链 (NfL)：NfL是轴突损伤的非特异性生物标志物，在多种神经退行性疾病中升高。尽管它不是AD特异性的，但高水平的NfL可能预示着神经退行性变的发生 92。
  • 脑源性tau (BD-tau)：传统血浆总tau（T-tau）主要来源于外周，与CSF T-tau相关性较差 92。最近开发出的脑源性tau (BD-tau) 是一种新的血液标志物，它选择性地结合来自大脑的tau，避免了外周表达的“大tau”异构体。血浆BD-tau与CSF T-tau和CSF BD-tau具有良好的相关性，且在区分AD与其他神经退行性疾病方面具有较高的特异性 92。这使得BD-tau有望成为血液中AT(N)框架的神经退行性标志物。
  • 代谢组学标志物：通过“组学”方法（如代谢组学）识别的生物标志物面板，可能提供更全面的信息，有望用于AD的早期诊断 84。例如，肠道菌群失调与AD病理学和认知功能下降之间存在关联 93。微生物物种特异性的分析发现，某些肠道菌群（如Akkermansia muciniphila）可能与淀粉样蛋白负荷降低相关，提示其潜在的保护作用 93。

影像学生物标志物 (PET)：
正电子发射断层扫描（PET）能够可视化脑内特定的AD病理特征，具有极高的诊断价值。

  • 淀粉样蛋白PET (Amyloid PET)：淀粉样蛋白PET使用特异性示踪剂（如[11C]PiB、[18F]florbetapir、[18F]flutemetamol、[18F]NAV4694）结合脑内淀粉样蛋白斑块，可以直接评估Aβ沉积的程度 81。淀粉样蛋白PET阳性结果是AD诊断生物学定义的重要组成部分 8194。
  • Tau蛋白PET (Tau PET)：Tau PET使用特异性示踪剂（如[18F]flortaucipir）检测脑内的tau蛋白缠结 81。Tau病理与认知功能下降的相关性比淀粉样蛋白病理更强，因此Tau PET在评估疾病进展和疗效方面具有重要价值 94。

不同标志物在疾病阶段的特异性与标准化挑战：

  • 疾病阶段特异性：淀粉样蛋白标志物（CSF Aβ42、血浆Aβ42/Aβ40、淀粉样蛋白PET）在前驱期甚至临床前阶段即可检测到异常，反映了AD病理的早期启动 81。Tau蛋白标志物（CSF P-tau、血浆p-tau、Tau PET）则更好地反映神经元损伤和认知功能下降的程度，与疾病进展的相关性更强 8188。神经退行性标志物（CSF T-tau、血浆NfL、BD-tau）则反映神经元丢失的程度，通常在疾病的中晚期更为显著。
  • 标准化挑战：尽管生物标志物在AD诊断中的价值日益凸显，但标准化仍然是主要挑战。不同实验室、不同检测平台之间的测量结果可能存在差异，影响结果的可比性 84。例如，血浆p-tau的测量方法和截断值仍需进一步标准化，以确保其在临床实践中的可靠性 8895。此外，生物标志物的结果需要结合患者的临床表现和其他检查结果进行综合判断，不能单独作为诊断依据 96。对于早期诊断，特别是用于抗淀粉样蛋白治疗的筛选，要求血浆生物标志物测试具有高敏感性（≥90%）和可接受的特异性（初级保健≥85%，二级保健≥75-85%） 95。这些挑战提示，未来的研究需要进一步关注生物标志物的标准化、验证以及在不同人群中的适用性，以便更好地将这些技术整合到临床实践中。

3.3 新兴诊断技术

随着人工智能（AI）和机器学习技术的飞速发展，阿尔茨海默病（AD）的诊断正经历一场革命，尤其是在早期识别和预测疾病进展方面。新兴诊断技术主要集中在利用AI分析复杂的神经影像数据、识别细微的语言模式变化，以及通过多模态数据融合来提高诊断的准确性。

AI在神经影像分析中的应用：
神经影像技术，特别是磁共振成像（MRI）和正电子发射断层扫描（PET），是评估大脑结构和功能变化的重要工具。然而，这些影像数据通常量大且复杂，传统的人工分析方法效率较低且容易受主观因素影响。AI，尤其是深度学习（Deep Learning, DL），能够从这些影像中自动提取和识别与AD相关的微小病理模式，从而显著提升诊断效率和准确性 979899100。

  • MRI分析：MRI能够提供大脑结构（如灰质萎缩、白质病变）和功能（如功能磁共振成像fMRI）的详细信息。深度学习模型，特别是卷积神经网络（CNNs），在分析结构MRI数据方面表现出色。通过训练大量的AD、轻度认知障碍（MCI）和健康对照组的MRI图像，AI模型能够识别出AD特有的脑萎缩模式，例如海马体和内嗅皮层的体积缩小 101102103。例如，有研究展示了深度学习模型利用单一的T1加权MRI扫描，即可在区分AD、MCI和健康对照方面达到高准确率，甚至可以预测MCI向AD的转化 102。另一项研究报告称，基于深度学习的MRI方法在诊断前驱期AD时，其曲线下面积（AUROC）达到了0.788，优于其他淀粉样蛋白（AUROC=0.702）或tau蛋白（AUROC=0.682）生物标志物 103。系统评价和荟萃分析也证实，深度学习在MRI图像分析中，对于AD和MCI的诊断表现出良好的敏感性和特异性，AUROC高达0.92 104。功能磁共振成像（fMRI）虽然数据复杂且噪声高，但结合深度学习技术，可以实现去噪和自动分类，通过检测脑部扫描模式来诊断AD 97。
  • PET分析：PET影像（如淀粉样蛋白PET和tau PET）能够直接反映AD的核心病理改变。AI技术可以协助分析这些PET图像，量化病理负荷，并预测疾病进展。结合MRI和PET数据的多模态深度学习模型能够捕获结构和功能上的病理变化，提高诊断的精准度 105106。
  • CT分析：虽然CT在AD诊断中不如MRI和PET常用，但在某些情况下仍可作为辅助手段。AI同样可以应用于CT图像分析，例如识别脑室扩大或弥漫性脑萎缩等改变。

语言模式识别：
语言障碍是AD的早期症状之一，AI技术在分析患者的言语和语言模式方面展现出巨大潜力。通过语音识别、自然语言处理（NLP）和机器学习算法，可以分析患者言语的语速、流畅性、词汇多样性、语法复杂性以及内容连贯性等特征，从中发现早期AD的细微线索。例如，AI可以识别出患者在命名困难、找词困难或重复性言语等方面的异常模式，这些都可能是AD的早期预警信号 98。这种非侵入性、低成本的诊断方法有望实现大规模筛查。

多模态数据融合对提高诊断准确性的作用：
AD的诊断往往需要整合来自不同维度的数据，包括临床表现、神经心理学测试、生物标志物（如CSF或血液指标）、遗传信息和神经影像数据。单模态数据可能无法全面捕捉疾病的复杂性，而多模态数据融合技术则可以将这些异构信息整合起来，构建更全面、更鲁棒的诊断模型 105106107。

  • 融合策略：多模态数据融合可以通过不同的策略实现，例如特征级融合（将不同模态提取的特征连接起来）、决策级融合（对不同模态的诊断结果进行加权或投票）或端到端融合（直接将多模态原始数据输入深度学习模型）105。
  • 案例研究：一项研究提出了一种3D多模态多尺度端到端分类器，通过整合MRI、PET、年龄和MMSE认知测试分数来增强AD诊断。该模型利用ResNet启发式架构和可训练的多尺度卷积缩放，将受试者分为正常对照（NC）、稳定型MCI（sMCI）、进展型MCI（pMCI）和AD四类，在ADNI数据集上表现出卓越的性能 105。另一项研究则展示了一个深度学习框架，能够接受临床信息、人口统计学、病史、神经心理学测试、神经影像和功能评估等多种数据组合，并与执业神经学家和神经放射学家的诊断准确性相当 106。
  • 优势：多模态数据融合的优势在于，它能够利用各模态数据的互补信息，弥补单一模态的不足，从而提高诊断的整体准确性、敏感性和特异性。例如，结构MRI可以揭示大脑萎缩，fMRI可以显示功能连接异常，PET可以量化淀粉样蛋白或tau蛋白负荷，而生物标志物则能提供分子水平的病理证据。将这些信息整合起来，AI模型能够更早、更准确地识别出疾病的迹象，并更好地预测疾病的进展和个体对治疗的反应 98107。

尽管AI在AD诊断中展现出巨大潜力，但仍面临一些挑战，包括数据隐私、AI模型的解释性、以及将AI工具无缝整合到临床工作流程的需求 98。未来的研究需要关注如何克服这些挑战，并进一步验证AI诊断模型的临床实用性。

4. 阿尔茨海默病的预防策略

鉴于阿尔茨海默病（AD）目前尚无治愈方法，预防和延缓疾病进展成为全球公共卫生领域的重要目标。研究表明，通过干预可调节的危险因素，全球约三分之一的痴呆症病例可以被预防或延迟 31。生活方式干预被认为是降低AD风险的有效途径，其中饮食模式和体育锻炼是两大核心组成部分。

4.1 生活方式干预

健康的生活方式在AD的预防中发挥着关键作用，特别是均衡的饮食习惯和规律的体育锻炼，已被证实能够通过多种机制提供神经保护作用。

饮食干预：地中海饮食与MIND饮食

饮食模式被广泛认为是影响AD风险的重要可调节因素 108。其中，地中海饮食（Mediterranean Diet, MeDi）和MIND饮食（Mediterranean-DASH Intervention for Neurodegenerative Delay）因其显著的神经保护作用而备受关注。

  • 地中海饮食（MeDi）的神经保护机制：
    地中海饮食以其富含水果、蔬菜、全谷物、豆类、坚果、橄榄油（作为主要脂肪来源）、适量鱼类和家禽，以及少量红肉和加工食品为特征 109。多项研究和荟萃分析一致表明，长期坚持地中海饮食与较低的AD发病风险相关 110111。具体而言，与对照组相比，严格遵循地中海饮食模式的个体患AD的风险降低了27% 111。其神经保护作用主要体现在以下几个方面：

    1. 抗氧化与抗炎作用：地中海饮食中丰富的多酚、类黄酮和维生素（如维生素C和E）具有强大的抗氧化特性，能中和自由基，减少氧化应激对神经元的损害 112113114。同时，这些生物活性成分能够抑制慢性炎症反应，减轻神经炎症，而神经炎症是AD病理生理学中的关键环节 114。
    2. 改善心血管健康：地中海饮食通过降低高血压、糖尿病和高胆固醇等心血管疾病的风险，间接保护大脑健康 112115。健康的血管系统能够确保充足的脑血流供应，维持神经元的正常功能，并促进Aβ的清除 2031。
    3. 肠道菌群调节：地中海饮食富含膳食纤维和益生元，有助于维持健康的肠道菌群平衡 110。健康的肠道菌群能够产生有益的代谢产物（如短链脂肪酸），这些物质可以通过肠脑轴影响大脑功能，减少神经炎症和氧化应激，从而发挥神经保护作用 110116。
    4. 提供关键营养素：地中海饮食提供了大量的ω-3脂肪酸（特别是鱼类中的长链ω-3脂肪酸，如DHA），它们对大脑结构和功能至关重要，有助于维持突触可塑性和认知功能 109113。此外，饮食中富含的B族维生素（如叶酸、B6、B12）有助于降低同型半胱氨酸水平，后者被认为是AD的危险因素 20112。

  • MIND饮食的神经保护机制：
    MIND饮食是地中海饮食和DASH（膳食方法阻止高血压）饮食的混合体，专门针对大脑健康进行了优化。它强调食用绿叶蔬菜、浆果、坚果、橄榄油、全谷物、鱼类和家禽，同时限制红肉、油炸食品、糕点、奶酪、黄油和人造黄油的摄入 112117118。MIND饮食在预防AD方面的效果可能优于单独的地中海饮食或DASH饮食 112。一项前瞻性研究对923名58至98岁的参与者进行了平均4.5年的随访，结果显示，严格遵循MIND饮食的个体患AD的风险显著降低，中度遵循者也能降低AD风险 117。特别是，严格遵循MIND饮食的个体AD风险降低高达53%，即使是中度遵循者也能降低35%的风险 117。其神经保护机制与地中海饮食有相似之处，但更侧重于对大脑有益的特定食物：

    1. 强效抗氧化与抗炎：MIND饮食特别强调浆果（富含花青素）和绿叶蔬菜（富含维生素E和叶酸）的摄入，这些食物具有强大的抗氧化和抗炎特性，能够直接对抗神经元的氧化损伤和炎症反应 112。
    2. 维持认知功能：MIND饮食通过提供大脑健康所需的关键营养素，如ω-3脂肪酸、维生素和矿物质，支持神经元功能和突触连接，从而减缓认知衰退 113118。
    3. 综合心血管益处：作为地中海饮食和DASH饮食的结合，MIND饮食在控制血压和血脂方面表现出色，有助于降低血管性痴呆和AD的风险。

体育锻炼的预防效果：

身体活动不足是AD的一个可调节风险因素 3031。规律的体育锻炼，包括有氧运动和抗阻训练，已被证明能有效降低AD的发生风险和延缓认知功能下降 31119120。一项荟萃分析发现，体育锻炼与较低的全因痴呆和AD发病率相关，即使在长期随访中也支持其作为可调节的保护性生活方式因素 120。体育锻炼的神经保护机制是多方面的：

  1. 改善脑血流：有氧运动能够增加脑血流量，优化大脑的氧气和营养供应。良好的脑血流有助于清除代谢废物，包括β-淀粉样蛋白，从而减少其在大脑中的积累 31。
  2. 促进神经营养因子分泌：体育锻炼能够刺激脑源性神经营养因子（BDNF）等多种神经营养因子的合成和释放。BDNF在神经元的生长、分化、存活以及突触可塑性方面发挥关键作用，对于维持认知功能至关重要 31。
  3. 减少炎症和氧化应激：规律运动能够调节免疫系统，减少慢性全身性炎症，并增强机体的抗氧化防御能力，从而减轻神经炎症和氧化应激对大脑的损害 31114。
  4. 调节Aβ和tau蛋白病理：动物模型和人体研究表明，体育锻炼可能有助于调节淀粉样β肽的代谢和清除，减少Aβ斑块的形成，并可能影响tau蛋白的病理改变 31。
  5. 增强认知储备：长期坚持体育锻炼可以增加大脑的灰质和白质体积，改善神经元连接，从而提高认知储备，使大脑在面对病理损伤时更能抵抗认知衰退 115121。一项研究发现，健康的生活方式（包括身体活动）与更好的认知功能相关，即使存在痴呆相关的脑部病理，也能提供认知储备 121。

综合来看，地中海饮食和MIND饮食通过提供抗氧化剂、抗炎物质和关键营养素，并改善心血管健康和肠道菌群，共同构成了预防AD的重要饮食策略。同时，规律的体育锻炼通过优化脑血流、促进神经营养因子分泌、减轻炎症和氧化应激等多种机制，为大脑提供了强大的保护。将这两种生活方式干预措施结合起来，有望最大程度地降低AD风险，延缓疾病的发生和进展。

4.2 慢性病管理与风险控制

阿尔茨海默病（AD）的预防不仅局限于积极的生活方式干预，还涉及对多种慢性疾病的有效管理。这些慢性病，特别是心血管危险因素，通过复杂机制影响大脑健康，并显著增加AD的风险。对这些可调节因素的早期干预和持续管理，被认为是延缓或预防AD发病的关键策略 19122。

高血压：
高血压是AD和血管性痴呆的一个重要危险因素，尤其是在中年时期（65岁以下）的高血压 122123。高血压通过多种途径损害大脑：

  1. 损害脑微循环：长期高血压会破坏脑微循环的结构和功能完整性，导致微血管稀疏、脑微血管内皮功能障碍和神经血管解耦联，从而损害脑血流供应 123。这种微循环损伤可能导致白质高信号、腔隙性梗死和微出血等神经放射学标志，这些都与认知能力下降相关 123。
  2. 血脑屏障破坏：高血压还会破坏血脑屏障（BBB），促进神经炎症并加剧淀粉样蛋白病理学 123。BBB功能的受损使得有害物质更容易进入大脑，并干扰Aβ的清除。
  3. 增加淀粉样蛋白沉积：研究表明，收缩压（SBP）和舒张压（DBP）的升高与淀粉样蛋白（Aβ）负荷、微出血和皮质微梗死显著相关，这些都是AD和血管性认知障碍的病理特征。例如，在一项针对中国社区老年人的研究中，高血压被发现与较高的Aβ负荷独立相关。
    干预策略：早期识别和有效控制高血压至关重要。通过药物治疗（如降压药）和生活方式调整（如地中海饮食、限盐、运动），将血压维持在正常水平，可以显著降低AD和血管性认知障碍的风险 123。加拿大的一项研究指出，中年高血压是痴呆的四大主要可调节风险因素之一，通过干预可预防约6.2%的痴呆病例 124。

糖尿病：
2型糖尿病（T2DM）与AD之间存在密切的联系，甚至有研究将AD称为“3型糖尿病”或“脑部糖尿病” 125126127128。T2DM对大脑健康的负面影响机制包括：

  1. 胰岛素抵抗与信号通路受损：T2DM以胰岛素抵抗为特征，这不仅影响外周血糖代谢，也影响大脑中的胰岛素信号通路 125129。大脑胰岛素抵抗与Aβ前体蛋白（APP）加工异常和Aβ清除受损有关，促进Aβ的积累 127。
  2. 神经炎症与氧化应激：慢性高血糖、胰岛素抵抗以及与T2DM相关的全身性炎症和氧化应激，会损害神经元，加速神经退行性病变 125130131。
  3. 血管损伤：T2DM还会导致微血管病变，影响脑血流，加剧脑缺血和血管性损伤，这与AD的病理学存在协同作用 126。
    干预策略：有效的血糖管理，包括饮食控制、规律运动和药物治疗，对于降低T2DM患者的AD风险至关重要 130。控制血糖波动、预防低血糖和高血糖事件，都有助于保护认知功能。糖尿病是痴呆的另一个重要可调节风险因素，加拿大研究显示其贡献了约3%的痴呆病例 124。

高胆固醇血症：
高胆固醇血症，尤其是在中年时期，被认为是AD的危险因素 122132。大脑是人体胆固醇含量最高的器官，其代谢与AD病理密切相关 132133。

  1. Aβ生成与清除：高胆固醇水平可能影响淀粉样前体蛋白（APP）的裂解，促进淀粉样蛋白β（Aβ）的生成，并抑制Aβ的清除，导致Aβ在脑内积累 132134。
  2. 氧化固醇作用：循环中的27-羟基胆固醇（27-hydroxycholesterol, 27-OHC）可以穿过血脑屏障，并在大脑中积累。27-OHC已被证明会影响Aβ的产生，并增加AD患者大脑中的水平 134。
  3. 脂质代谢基因：载脂蛋白E（APOE）ε4等位基因是AD最强的遗传风险因素，它在脂质代谢中发挥关键作用，通过影响胆固醇和Aβ的转运与清除，显著增加AD风险 135。
    干预策略：通过健康饮食（如地中海饮食）、规律运动和必要时使用降脂药物（如他汀类药物）来管理血脂水平，对于降低AD风险具有重要意义。

听力损失：
听力损失已被确定为AD的一个可调节危险因素 122124。虽然其确切机制仍在研究中，但以下几种假说被广泛讨论：

  1. 认知负荷增加：听力受损的个体需要付出更多的认知努力来理解语言，这可能耗竭认知资源，导致其他认知功能（如记忆）下降。
  2. 社会隔离：听力损失可能导致社交活动减少和社会隔离，进而影响认知刺激和心理健康，增加痴呆风险。
  3. 共同的神经病理：听力损失和AD可能共享一些神经病理机制，例如脑部萎缩或炎症。
    干预策略：早期诊断和干预听力损失，如佩戴助听器或人工耳蜗，可能有助于降低痴呆风险。一项研究显示，中年听力损失是加拿大痴呆的第二大可调节风险因素，贡献了约6.5%的痴呆病例 124。

睡眠障碍：
睡眠障碍，特别是慢性失眠和睡眠呼吸暂停，与AD风险增加相关。

  1. 淋巴系统功能障碍：睡眠期间，大脑的淋巴系统（glymphatic system）会更有效地清除代谢废物，包括Aβ。睡眠不足或睡眠质量差会损害淋巴系统的功能，导致Aβ在脑内积累，加速AD病理进展。
  2. 神经炎症：慢性睡眠障碍会增加全身性炎症，并可能导致中枢神经系统的神经炎症，从而损害神经元。
    干预策略：改善睡眠质量，治疗睡眠呼吸暂停等睡眠障碍，有助于维持大脑的健康代谢和清除机制。加拿大的一项研究发现，晚年睡眠障碍也是痴呆的一个可调节风险因素，贡献了约3%的痴呆病例 124。

其他可调节因素：
除了上述因素，吸烟、肥胖、抑郁症、缺乏体力活动和低教育水平也被认为是AD的重要可调节风险因素 1935122136。例如，吸烟会增加氧化应激和炎症，损害血管功能；肥胖，特别是在中年时期，与AD风险显著相关；抑郁症可能是AD的早期症状，也可能是其风险因素；缺乏体力活动则与多种心血管危险因素和认知储备不足相关。

总结：
综合来看，对高血压、糖尿病、高胆固醇、听力损失和睡眠障碍等慢性疾病进行早期、积极的管理和干预，不仅能改善整体健康状况，更能有效降低AD的发生风险。这些因素的有效控制，结合健康的生活方式，为AD的预防提供了多维度的策略。据估计，通过积极干预这些可调节风险因素，全球约三分之一的AD病例可能得以预防 136。

4.3 认知储备提升

认知储备（Cognitive Reserve, CR）是指个体大脑在面对病理损伤或衰老时，能够通过更有效或更灵活的认知过程来维持认知功能的能力。高认知储备的个体，即使大脑存在一定程度的神经病理变化，也能表现出相对正常的认知功能，从而延缓痴呆的临床表现 137。提升认知储备是阿尔茨海默病（AD）预防策略的重要组成部分，主要通过教育、职业复杂度和终身学习等活动来积累。

教育
教育程度是影响认知储备最直接且被广泛研究的因素之一。多项研究表明，受教育年限越长，个体患AD的风险越低 138139140。孟德尔随机化分析发现，基因决定的受教育年限增加与AD风险呈负相关（每增加一个标准差的受教育年限，AD风险降低30%）141。这种保护作用可能通过多种机制实现：

  1. 神经可塑性与脑结构优化：教育可以促进大脑皮层区域的面积、体积和局部回旋指数增加，形成更高效和更具弹性的神经网络 141。这意味着高教育水平的个体拥有更强大的“神经储备”，能够更好地应对神经退行性病变带来的损伤。
  2. 认知策略与效率：高教育背景的个体通常能发展出更灵活、更有效的认知策略来处理信息，即使大脑功能受损，也能利用这些策略弥补缺陷 137。
  3. 社会经济地位与健康行为：教育水平通常与更高的社会经济地位、更健康的生活方式以及更好的医疗保健获取途径相关联，这些因素也可能间接降低AD风险 139。然而，即使排除这些混杂因素，教育对AD的保护作用依然显著 138。

职业复杂度
职业复杂度是指工作中涉及的认知要求、决策制定和问题解决的复杂程度。从事认知要求高的职业（如需要高数据处理、人际互动和实质性复杂性工作的职业）被认为能有效积累认知储备 140142。

  1. 大脑持续激活：复杂的工作环境能持续刺激大脑，促进神经元连接和突触可塑性，从而增强大脑的适应性和抵抗力 143。
  2. 降低痴呆风险：一项对来自6个国家9个国际数据集共10195名参与者的荟萃分析显示，教育和职业复杂度均与延长无痴呆生存时间独立相关。职业复杂度甚至介导了28%教育对痴呆风险的保护作用 142。另一项系统回顾和荟萃分析发现，从事脑力工作可使轻度认知障碍（MCI）风险降低44% 144。
  3. 增强干预效果：研究发现，高职业复杂度与更好的基线认知功能相关。在多领域干预试验中，例如芬兰老年干预研究（FINGER），虽然高职业复杂度不显著影响干预对认知的总体效果，但与执行功能的改善程度相关 143。

终身学习与休闲活动
除了早期教育和职业，贯穿生命周期的认知刺激活动，如学习新技能、阅读、玩益智游戏、社交互动等，都能持续提升认知储备 140。

  1. 维持大脑活力：终身学习能够维持大脑的活跃状态，延缓认知衰退。新的学习经历可以促进新的神经通路形成，增强大脑应对损伤的能力。
  2. 综合保护效应：一项荟萃分析发现，高认知储备（通过教育、职业复杂度、体力活动和社交健康等综合指标衡量）与降低47%的MCI或痴呆进展风险相关 145。即使在已存在AD相关结构性病理和生物标志物的情况下，高认知储备仍能保护个体免受认知功能下降的影响 145146147。
  3. 应激调节作用：近期研究显示，认知储备对认知的益处可能受到生理应激的调节。在记忆门诊患者中，高认知储备与更好的认知功能相关，但当考虑到皮质醇水平等应激指标时，这种关联有所减弱，提示有效管理应激对维持认知储备效益的重要性 146。

认知训练在高危人群中的预防潜力
认知训练是一种系统性的干预措施，旨在通过重复性练习和特定任务来改善或维持认知功能，特别适用于轻度认知障碍（MCI）等高危人群。

  1. 记忆游戏与多任务练习：例如，一项针对遗忘型MCI（aMCI）患者的随机对照试验发现，使用iPad进行记忆游戏认知训练（4周内8小时）显著改善了患者的情景记忆。训练组在剑桥神经心理学测试自动电池配对联想学习任务中的错误次数和所需试验次数均显著减少，并且在简易精神状态检查（MMSE）、简短视空间记忆测试和冷漠评估量表上也观察到显著改善 148。
  2. “游戏化”训练：研究表明，“游戏化”的认知训练能够最大程度地提高患者的参与度和积极性，增强其继续训练的动机，并提升自信心和自我评价的记忆能力 148。这提示，有趣且富有挑战性的认知训练形式可能比传统训练更有效。
  3. 结合药理治疗：认知训练可以作为药物治疗的有效补充，尤其是在aMCI和轻度AD患者中，有望进一步延缓疾病进展 148。

总而言之，通过提供高质量的教育、选择具有挑战性的职业、保持终身学习的习惯，并辅以系统性的认知训练，可以有效提升个体的认知储备，从而增强大脑对AD病理损伤的抵抗力，延迟或预防AD的临床发病。

5. 阿尔茨海默病的治疗进展与展望

阿尔茨海默病（AD）的治疗在过去几十年中取得了显著进展，但目前仍无治愈方法。现有的治疗策略主要分为两大类：症状缓解药物和疾病修饰疗法（Disease Modifying Therapies, DMT）。症状缓解药物旨在改善或稳定患者的认知和行为症状，而DMT则致力于延缓或阻止疾病的病理进程。本节将详细探讨这些治疗进展及未来展望。

5.1 症状缓解药物

症状缓解药物是目前临床上最常用的AD治疗方案，主要通过改善神经递质功能来减轻认知和行为症状。这些药物并不能改变疾病的根本病理进程，但可以显著改善患者的生活质量。

胆碱酯酶抑制剂（ChEIs）：
胆碱酯酶抑制剂（ChEIs）是AD治疗的一线药物，其作用机制是通过抑制乙酰胆碱酯酶（acetylcholinesterase）的活性，减少神经递质乙酰胆碱（acetylcholine）的分解，从而增加脑内乙酰胆碱的水平。乙酰胆碱是与学习、记忆和认知功能密切相关的重要神经递质，AD患者大脑中胆碱能神经元的缺失和乙酰胆碱水平的降低是导致认知障碍的关键因素之一 149。目前市场上的ChEIs主要有多奈哌齐（Donepezil）、卡巴拉汀（Rivastigmine）和加兰他敏（Galantamine） 150。

  • 多奈哌齐（Donepezil）：
    多奈哌齐是一种可逆性的乙酰胆碱酯酶抑制剂，已被广泛应用于轻度、中度和重度AD的治疗 151。
    • 作用机制：主要通过选择性抑制脑内的乙酰胆碱酯酶，提高突触间隙乙酰胆碱的浓度，从而增强胆碱能神经传递，改善认知功能。
    • 临床疗效：多项研究和系统评价证实，多奈哌齐能显著改善AD患者的认知功能（如ADAS-Cog评分、MMSE评分）和日常活动能力，并改善临床医生评估的整体临床状态 151152153。一项对8257名参与者进行分析的系统评价显示，在治疗24至26周后，多奈哌齐（10 mg/天）与安慰剂相比，在认知功能（ADAS-Cog评分平均改善2.67分，MMSE评分平均改善1.05分）和日常生活能力方面均表现出显著益处 151。在中国的AD患者中，多奈哌齐也显示出良好的疗效和安全性，并可能对AD生物标志物（如海马萎缩、Aβ和tau）产生影响 154。
    • 临床局限性：尽管多奈哌齐能够改善症状，但其效果通常是轻微且有限的，并且不能阻止疾病的进展或逆转神经元的损伤 149150。患者可能会经历胃肠道副作用，如恶心、呕吐、腹泻等，导致约24%的患者因不良事件退出研究 151。此外，不同剂量的多奈哌齐（如5 mg/天、10 mg/天和23 mg/天）在疗效上差异不大，但高剂量可能伴随更高的不良事件发生率 151。

NMDA受体拮抗剂：
N-甲基-D-天冬氨酸（NMDA）受体拮抗剂代表了AD治疗的另一种策略。NMDA受体是谷氨酸能神经递质系统的重要组成部分，谷氨酸在学习和记忆中发挥关键作用。然而，AD患者中可能存在谷氨酸功能异常，导致谷氨酸毒性，进而引起神经元损伤和死亡 155156。

  • 美金刚（Memantine）：
    美金刚是目前唯一获批用于治疗中度至重度AD的NMDA受体拮抗剂 157158。
    • 作用机制：美金刚通过非竞争性地拮抗NMDA受体，调节异常的谷氨酸能神经传递。在AD中，淀粉样β肽寡聚体可直接激活NMDA受体，导致细胞内钙离子超载和神经元死亡 159160。美金刚能够阻断这种异常的持续激活，从而减轻谷氨酸兴奋性毒性，保护神经元 156。
    • 临床疗效：美金刚在改善中度至重度AD患者的认知功能、日常活动能力和行为症状方面显示出一定的疗效 161162。它通常与ChEIs联合使用，以提供更全面的症状控制 150163。一项系统评价指出，美金刚对阵发性偏头痛的预防性治疗也可能有效 157。
    • 临床局限性：与ChEIs类似，美金刚也仅仅是症状性治疗，无法阻止或逆转AD的神经退行性进程 149150164。其改善作用通常是中等程度的，且可能伴随轻度至中度不良反应，如嗜睡、头晕、头痛和恶心等 157163。在多重用药的老年患者中，美金刚单药治疗可能比联合治疗更具耐受性 163。

总结：
胆碱酯酶抑制剂和NMDA受体拮抗剂是AD症状缓解治疗的基石。它们通过不同的机制改善患者的认知功能和日常表现，但在疾病修饰方面存在显著局限性。这些药物的研发为AD患者带来了重要的希望，并为后续更具靶向性的疾病修饰疗法提供了研究基础。然而，对更有效、副作用更小的治疗方案的探索仍在持续。

5.2 疾病修饰疗法（DMT）

疾病修饰疗法（Disease Modifying Therapies, DMT）代表了阿尔茨海默病（AD）治疗领域最重要的进展方向。与仅能缓解症状的药物不同，DMT旨在通过靶向疾病的根本病理生理过程来减缓或停止疾病的进展。近年来，针对β-淀粉样蛋白（Aβ）的抗体疗法取得了突破性进展，为早期AD患者带来了新的希望。

抗淀粉样抗体：Donanemab与Lecanemab

多种抗淀粉样蛋白的单克隆抗体（mAbs）已被开发，它们通过清除大脑中的Aβ斑块来达到疾病修饰的目的 165166167168。其中，donanemab和lecanemab是目前获得美国FDA加速批准或完全批准的代表性药物，并已在一系列III期临床试验中展现出减缓临床进展的潜力 167169170。

  • Lecanemab（商品名：Leqembi）：

    • 作用机制：Lecanemab是一种靶向可溶性Aβ原纤维的单克隆抗体，Aβ原纤维被认为是AD神经毒性的关键启动因子 165166。通过结合并清除这些原纤维，lecanemab旨在减少Aβ斑块的形成和积累，从而阻止或减缓下游的病理进程 165。
    • III期临床试验结果：Lecanemab的CLARITY AD III期临床试验结果显示，该药物能够显著减缓早期AD患者的认知和功能衰退。与安慰剂组相比，lecanemab组在主要临床终点（如CDR-SB和ADAS-Cog）上表现出约27%的临床进展减缓 167。这一结果证实了Aβ清除与临床获益之间的关联，标志着AD治疗的一个重要突破 169。通过正电子发射断层扫描（PET）检测，lecanemab治疗显著降低了患者脑内的Aβ斑块负荷 167。
    • 适用人群：Lecanemab适用于具有Aβ病理证实的早期症状性AD患者（包括轻度认知障碍和轻度痴呆阶段） 167170。这要求患者在接受治疗前必须通过淀粉样蛋白PET扫描或脑脊液（CSF）检测证实Aβ沉积的存在 170。一项评估AD临床试验中种族和民族多样性的研究发现，不同人群在淀粉样生物标志物资格方面存在差异，这可能影响lecanemab等药物的适用性 171。
    • 安全性（ARIA风险）：Lecanemab最常见的副作用是淀粉样蛋白相关影像学异常（Amyloid-Related Imaging Abnormalities, ARIA），包括水肿或渗出（ARIA-E）和微出血或含铁血黄素沉积（ARIA-H） 165172。ARIA通常在治疗早期发生，多数情况下为无症状，但也可引起头痛、恶心、意识模糊等症状，少数情况下可导致严重并发症，甚至死亡 173。在lecanemab的试验中，ARIA-E的发生率约为12.5%，ARIA-H的发生率约为17% 167。具有APOE ε4基因携带者，尤其是APOE ε4纯合子，ARIA的风险显著增加 172174。因此，在治疗过程中需要进行定期的MRI监测，以早期发现并管理ARIA 167170。

  • Donanemab（商品名：Kisunla）：

    • 作用机制：Donanemab是一种特异性靶向已经沉积的Aβ斑块中焦谷氨酸Aβ（AβpE3-42）的单克隆抗体，这种Aβ形式被认为是Aβ斑块形成的核心成分 166168。与lecanemab不同，donanemab旨在清除已形成的老年斑，而非可溶性原纤维 166。其独特的靶向机制使其能够有效清除大脑中的Aβ斑块 74。
    • III期临床试验结果：Donanemab的TRAILBLAZER-ALZ 2 III期临床试验结果显示，在早期症状性AD患者中，donanemab能够显著减缓疾病的临床进展，减缓幅度约为30% 74。具体而言，在具有低/中度tau病理的患者中，iADRS评分的下降显著少于安慰剂组（donanemab组下降6.02分，安慰剂组下降9.27分），差异为3.25分，CDR-SB评分的差异为-0.67分 74。这些结果支持donanemab的疾病修饰潜力 74。
    • 适用人群：Donanemab的临床试验主要招募了具有早期症状性AD，并根据PET成像显示具有淀粉样蛋白和低/中度或高度tau病理的患者 74。结果表明，donanemab对低/中度tau负荷的患者效果更佳 74175。对于高tau负荷的患者，其疗效可能有限，这提示了tau蛋白负荷在选择DMT治疗中的重要性 175。低tau负荷在Aβ阳性的无症状或受损个体中相对常见，并且与年龄较大、男性和更大的心血管风险等合并症相关，这些发现对Aβ和tau修饰疗法的个体选择具有指导意义 175。
    • 安全性（ARIA风险）：Donanemab也存在ARIA的风险。在TRAILBLAZER-ALZ 2试验中，donanemab组有24.0%的患者发生ARIA-E 74。其中，52名（6.1%）患者出现症状性ARIA-E，而安慰剂组为0 74。试验中，donanemab组有3例死亡被认为与治疗相关，而安慰剂组有1例 74。这些安全性数据强调了在治疗期间对患者进行严密监测的必要性，特别是对APOE ε4携带者，ARIA风险更高 172174。

总结：
抗淀粉样抗体为AD治疗开辟了新的篇章，首次证明通过清除Aβ斑块可以实现临床进展的减缓 167169。然而，这些DMT的应用并非没有挑战，主要包括ARIA风险的管理、对特定患者群体（如不同tau负荷水平）的适用性、以及治疗的成本和可及性等 170。未来的研究将继续致力于提高DMT的疗效、降低副作用，并探索更安全的给药方式（如口服小分子药物），以期为更广泛的AD患者带来福祉 168。

5.3 新兴治疗策略

阿尔茨海默病（AD）的治疗挑战促使研究人员不断探索创新的治疗策略，以克服现有疗法的局限性。这些新兴策略涵盖了从外科手术干预到先进药物递送技术，再到神经内分泌调节等多个维度，旨在更有效地靶向AD病理、提高药物疗效并减少副作用。

5.3.1 神经淋巴手术

淋巴系统，特别是脑部的淋巴系统，在清除脑内代谢废物（如淀粉样-β蛋白和磷酸化tau蛋白）中发挥着关键作用。随着年龄增长，这些清除途径的功能逐渐下降，导致废物堆积，这与神经退行性疾病（如AD和帕金森病）的发生发展密切相关 176。近年来，神经淋巴手术作为一种创新方法，旨在通过增强脑部淋巴清除功能来治疗神经退行性疾病，引发了广泛关注。

  • 作用机制：神经淋巴手术主要通过淋巴静脉吻合术（Lymphatico-venous Anastomoses, LVA）来增强脑淋巴回流。这种手术方式通常针对深部颈部淋巴管，建立淋巴管与静脉之间的吻合，从而促进脑脊液（CSF）和间质液（ISF）中代谢废物的排出 176177。由于AD与脑脊液清除系统功能障碍相关，增强脑部的废物清除能力有望减缓甚至逆转Aβ和tau蛋白的积累，减轻神经毒性。有研究将淋巴功能障碍视为一种“脑水肿”，认为LVA在治疗外周水肿方面已显示出潜力，可能也适用于脑水肿 176。
  • 研究现状：目前，关于神经淋巴外科技术改善中枢神经系统（CNS）代谢废物清除途径的临床数据仍然有限，但初步研究结果令人鼓舞 176。多项研究探索了一种涉及深部颈部淋巴管的创新技术，即通过淋巴静脉吻合术来促进清除，以治疗AD或帕金森病 176。在临床前模型中，例如大鼠颈部淋巴结静脉吻合术（LNVA）模型，研究人员成功建立了可重复的显微外科平台，并证实该手术能有效增强脑淋巴清除功能 177。这种手术模型不仅为淋巴和整形外科提供了先进的培训平台，也为进一步研究淋巴功能及其在神经退行性疾病中的作用提供了精确的结构性方法 177。
  • 潜力与挑战：神经淋巴手术代表了一种有前途的AD治疗途径，通过直接干预脑部废物清除机制来解决AD的核心病理。然而，该领域仍处于早期阶段，需要更多的临床证据来验证其疗效和安全性。手术的侵入性、潜在并发症以及患者选择标准等问题也需要进一步研究和解决。

5.3.2 纳米药物递送

血脑屏障（Blood-Brain Barrier, BBB）是药物进入大脑的主要障碍，严重限制了传统AD治疗药物的疗效 178179180181。纳米药物递送系统（Nanotechnology-based Drug Delivery Systems）通过设计、表征、生产和应用纳米尺度的药物递送载体，为克服BBB挑战、实现药物高效靶向脑部提供了革命性的解决方案 178180181182。

  • 作用机制：纳米颗粒能够通过多种机制穿透BBB，包括内吞作用、转细胞作用，或通过修饰表面配体与BBB上的受体结合进行受体介导的转运 183184。一旦进入大脑，纳米药物可以精确地将治疗性分子（如抗淀粉样蛋白药物、抗氧化剂、神经营养因子、小干扰RNA等）递送到受损的神经元或病理区域，提高局部药物浓度，同时减少全身副作用 182185。
  • 纳米载体类型：目前研究的纳米载体包括聚合物纳米颗粒、固体脂质纳米颗粒、纳米结构脂质载体、微乳液、纳米乳液以及脂质体等 178183。
    • 脂质体：脂质体因其生物相容性好、灵活性高，以及能够携带多种治疗分子穿过BBB并进入脑细胞的潜力而备受关注 183。通过表面修饰，例如结合脑渗透肽、Aβ靶向配体（如磷脂酸、姜黄素）或逆转肽，可以进一步增强脂质体穿透BBB和靶向Aβ聚集体的能力 183。
    • 其他纳米颗粒：基于纳米颗粒的药物递送系统，如二氧化硅纳米颗粒负载姜黄素、硒纳米颗粒负载白藜芦醇等，已被证明能够有效穿过BBB并靶向神经炎症，从而潜在减缓疾病进展和改善认知功能 181。此外，脑渗透性NEP（neprilysin）通过纳米技术递送，在小鼠模型中显示出降解单体Aβ和减少Aβ寡聚体的潜力 186。
  • 研究现状：纳米药物在AD治疗的临床前研究中显示出巨大潜力，通过高效、靶向的药物递送，有望提高药物的生物利用度和疗效 178182。除了药物递送，纳米技术还在AD的早期诊断方面发挥作用 182185。
  • 潜力与挑战：纳米药物递送系统有望彻底改变AD的治疗格局，解决BBB这一长期障碍。然而，该领域仍面临诸多挑战，包括纳米材料的生物安全性、长期毒性、大规模生产的成本效益，以及如何确保药物在脑部的精确靶向和有效释放。此外，需要更深入的研究来理解纳米颗粒在体内的代谢途径和潜在的免疫反应。

5.3.3 催产素调节PV中间神经元功能

社会认知障碍，如共情能力减退和社交退缩，是AD的早期非认知症状之一，并与大脑中PV（Parvalbumin）中间神经元的功能障碍密切相关 58。催产素（Oxytocin, OT）作为一种神经肽，被认为可能通过调节PV中间神经元功能，改善这些早期症状，从而为AD治疗提供新的思路。

  • 作用机制：PV中间神经元是抑制性神经元，在维持大脑皮层兴奋/抑制平衡、调节神经回路活动以及高级认知功能中发挥关键作用 58。AD早期，Aβ和tau病理可能导致PV中间神经元功能受损，进而影响社会认知和记忆。催产素被认为是PV中间神经元的有效调节剂，可以增强其功能。通过调节PV中间神经元，催产素可能有助于恢复神经回路的正常活动，改善与社会认知和记忆相关的神经功能 58。
  • 研究现状：虽然催产素在多种神经精神疾病（如自闭症谱系障碍）的临床试验中显示出积极效果，但其在AD治疗中的潜力仍处于探索阶段 58。研究表明，催产素对AD病理可能具有有益影响，例如调节PV中间神经元的活性，从而可能间接改善社会认知障碍 58。
  • 潜力与挑战：靶向PV中间神经元并利用催产素调节其功能，为AD早期社会认知障碍的治疗提供了一种新颖的策略。这种方法不仅可能改善患者的社会互动能力和生活质量，还可能通过减轻与社会认知相关的神经病理来延缓疾病进展。然而，关于催产素在AD中的具体作用机制、最佳给药途径和剂量，以及其在AD患者中的长期疗效和安全性，仍需大量的基础和临床研究来验证。

这些新兴治疗策略，无论是通过物理手段增强废物清除，还是通过先进技术递送药物，亦或是通过神经肽调节神经回路，都代表了AD治疗领域的前沿探索。它们有望克服现有疗法的局限，为AD患者带来更有效的、更全面的治疗方案。

5.4 综合管理与支持治疗

阿尔茨海默病（AD）的综合管理是一个多维度、以患者为中心的治疗模式，它不仅关注疾病本身的症状控制和进展延缓，还强调通过非药物干预来改善行为和精神症状（Behavioral and Psychological Symptoms of Dementia, BPSD），并依赖多学科团队的协作来提供全面的支持和护理。由于AD目前尚无治愈方法，且疾病修饰疗法仍在发展中，因此，有效的综合管理和支持治疗对于提升患者和照护者的生活质量至关重要。

行为症状的非药物干预

行为和精神症状（BPSD），如抑郁、激越、冷漠、焦虑和睡眠障碍等，在AD患者中普遍存在，显著影响患者的生活质量并增加照护者的负担 187。非药物干预是处理BPSD的首选方法，尤其是在启动药物治疗之前 187。这些干预措施通常是个性化的，并基于对患者行为触发因素的理解。

  1. 情绪条件反射训练：
    情绪条件反射训练旨在通过创造积极、支持性的环境，帮助患者重新建立积极的情绪关联。例如，通过播放患者熟悉的、愉悦的音乐，进行回忆疗法（reminiscence therapy），或参与艺术、园艺等有意义的活动，可以唤起患者的积极情绪，减少焦虑和激越。有研究表明，基于情绪唤起（emotional arousal）的干预措施可以减少AD患者的游荡行为，并改善其情绪状态。通过营造安全、熟悉的环境，提供一致的日常安排，可以减少患者的困惑和不适，从而降低激越行为的发生。
  2. 环境调整：
    优化患者所处的物理和社会环境对于管理BPSD至关重要。这包括减少噪音和刺激，提供充足的自然光线，确保环境安全，以及提供熟悉的物品和照片，以帮助患者定向并减少焦虑。例如，去除可能导致跌倒的障碍物，确保厕所易于找到且标识清晰，都可以显著提高患者的舒适度和安全性。
  3. 个性化照护：
    了解患者的个人历史、兴趣爱好和习惯，有助于设计个性化的干预方案。例如，对于曾经喜欢阅读的患者，提供适合其认知水平的读物；对于喜欢户外活动的患者，安排安全的户外散步。个性化的照护可以增加患者的参与度，减少挫败感，从而缓解负面行为。
  4. 认知和感觉刺激：
    轻度的认知刺激活动，如记忆游戏、拼图、简单的家务活动等，可以帮助维持患者的残余认知功能，并提供结构化的日常活动。感觉刺激，如芳香疗法、按摩和接触宠物（宠物疗法），也被证明对缓解焦虑和激越有益。

多学科团队在全程管理中的重要性

AD的复杂性要求一个整合的多学科团队提供全面的护理，以应对患者生理、心理、社会和功能方面的多重需求。这个团队通常包括：

  1. 神经科医生：
    负责AD的诊断、药物治疗（如症状缓解药物和疾病修饰疗法）、评估疾病进展，并管理神经系统并发症。他们是患者病程中的主要医疗联系人，并协调其他专科的参与。
  2. 心理科医生/精神科医生：
    负责评估和管理患者的心理健康问题，如抑郁、焦虑、激越和精神病性症状。他们可以提供药物治疗、认知行为疗法（CBT）以及其他心理支持，以改善患者的情绪和行为状态。
  3. 护理人员：
    提供日常护理、用药管理、协助日常生活活动（ADLs）和工具性日常生活活动（IADLs），并对家属进行照护培训。护士在监测患者症状变化、评估药物副作用以及提供情感支持方面发挥关键作用。
  4. 社会工作者：
    帮助患者和家属获取社会资源、福利和社区支持服务，解决经济、法律和住房等方面的实际问题。他们也提供咨询和支持，帮助家庭应对疾病带来的挑战。
  5. 职业治疗师（OT）：
    评估患者的日常生活能力，并提供适应性策略和辅助设备，帮助患者保持尽可能高的独立性。例如，针对认知障碍患者，职业治疗师可以教授简化任务、使用视觉提示等方法。
  6. 物理治疗师（PT）：
    通过运动训练，帮助患者维持身体功能、平衡能力和活动范围，预防跌倒，改善步态和肢体功能，从而提高生活质量。
  7. 营养师：
    针对AD患者的特殊营养需求，提供饮食建议，预防营养不良，并针对吞咽困难等问题提供解决方案。地中海饮食和MIND饮食等健康饮食模式的推广，也需要营养师的专业指导。
  8. 其他支持人员：
    包括药师（管理药物相互作用）、言语治疗师（改善沟通和吞咽功能）、艺术治疗师、音乐治疗师等，共同为患者提供全方位的支持。

多学科团队的协作确保了患者能够获得持续、协调和全面的照护，不仅关注疾病的医学治疗，还兼顾患者的心理健康、社会需求和功能独立性。这种整合性管理方法不仅能改善患者的临床结局，还能显著减轻照护者的负担，提高整个家庭的生活质量。

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参考文献

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L A Farrer, L A Cupples, J L Haines, et al.
JAMA. 1997;278(16):1349-56.
OBJECTIVE: To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. DATA SOURCES: Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. MAIN OUTCOME MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. RESULTS: Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. CONCLUSIONS: The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.

3APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches.PubMed

Alberto Serrano-Pozo, Sudeshna Das, Bradley T Hyman
Lancet Neurol. 2021 Jan;20(1):68-80. doi: 10.1016/S1474-4422(20)30412-9.
The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE ε2 allele the strongest genetic protective factor after multiple large scale genome-wide association studies and genome-wide association meta-analyses. However, no therapies directed at APOE are currently available. Although initial studies causally linked APOE with amyloid-β peptide aggregation and clearance, over the past 5 years our understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption. Because all these pathological processes can potentially contribute to cognitive impairment, it is important to use this new knowledge to develop therapies directed at APOE. Several therapeutic approaches have been successful in mouse models expressing human APOE alleles, including increasing or reducing APOE levels, enhancing its lipidation, blocking the interactions between APOE and amyloid-β peptide, and genetically switching APOE4 to APOE3 or APOE2 isoforms, but translation to human clinical trials has proven challenging.

4Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.PubMed

Yu Yamazaki, Na Zhao, Thomas R Caulfield, et al.
Nat Rev Neurol. 2019 Sep;15(9):501-518. doi: 10.1038/s41582-019-0228-7. Epub 2019 Jul 31.
Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

5Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence.PubMed

Mona Hersi, Brittany Irvine, Pallavi Gupta, et al.
Neurotoxicology. 2017 Jul;61:143-187. doi: 10.1016/j.neuro.2017.03.006. Epub 2017 Mar 29.
A systematic review was conducted to identify risk factors associated with the onset and progression of Alzheimer's disease (AD). Moderate and high quality systematic reviews were eligible for inclusion. Primary studies reporting on non-genetic risk factors associated with neuropathologically or clinically confirmed AD were considered. Eighty one systematic reviews reporting on AD onset and 12 reporting on progression satisfied the eligibility criteria. Four hundred and thirty-two relevant primary studies reporting on onset were identified; however, only those published between 2010 and 2012 (n=65) were included in the qualitative synthesis. Several factors including statins, light-to-moderate alcohol consumption, compliance with a Mediterranean diet, higher educational attainment, physically and cognitively stimulating activities, and APOE ε2 appeared to be associated with a decreased risk of AD onset. The evidence was suggestive of an increased risk of AD associated with head injury in males, age, diabetes mellitus, conjugated equine estrogen use with medroxyprogesterone acetate, current smoking, and lower social engagement. With respect to genetic factors, APOE ε4 remained the strongest predictor of AD. Physical and cognitive activities were associated with a beneficial effect on cognitive function and other indicators of dementia progression while higher educational attainment was associated with faster cognitive decline. Although suggestive of an association, the current evidence for a majority of the identified putative factors for AD onset and progression was weak, at best due to conflicting findings across studies or inadequate evidence. Further research is required to confirm the etiological or protective role of a number of risk factors.

6Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.PubMed

E H Corder, A M Saunders, W J Strittmatter, et al.
Science. 1993 Aug 13;261(5123):921-3. doi: 10.1126/science.8346443.
The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

7ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease.PubMed

Yonghe Li, Jesse R Macyczko, Chia-Chen Liu, et al.
Neurobiol Aging. 2022 Jul;115:20-28. doi: 10.1016/j.neurobiolaging.2022.03.011. Epub 2022 Mar 22.
APOE4 is the first identified genetic risk factor and remains as the strongest predictor for late-onset Alzheimer's disease (AD). Studies of AD patients, AD patient-specific induced pluripotent stem cell-derived neurons and cerebral organoids, and human apoE4-expressing and apoE-deficient mouse models clearly demonstrate that apoE4 provokes neuroinflammation, impairs cerebrovasculature, and exacerbates amyloid and tau pathologies. ApoE expression is greatly up-regulated in disease-associated microglia in mouse models of amyloidosis and in human microglia from AD brains. Importantly, genetic knock-down or depletion of apoE in mice greatly attenuates neuroinflammation and alleviates amyloid and tau pathologies. Similar beneficial effects can be achieved when apoE reduction is induced by the overexpression of apoE metabolic receptor LDLR. Toward therapeutic implications, administration of apoE antisense oligonucleotides or apoE siRNAs leads to significant pharmacologic effects, i.e., significant alleviation of AD pathologies in mouse models. Therefore, apoE reduction represents a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele. In this review, we summarize evidence and rationale on why and how we target apoE4 reduction for AD therapy.

8Exercise and estrogen: common pathways in Alzheimer's disease pathology.PubMed

Ahmed Bagit, Grant C Hayward, Rebecca E K MacPherson
Am J Physiol Endocrinol Metab. 2021 Jul 1;321(1):E164-E168. doi: 10.1152/ajpendo.00008.2021. Epub 2021 May 31.
Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive declines in cognitive function. Current epidemiological data indicate significant sex-linked disparities, where females have a higher risk of developing AD compared with male counterparts. This disparity necessitates further investigations to uncover the pathological and molecular factors influencing these sex differences. Although the underlying pathways behind this observed disparity remain elusive, recent research points to menopausal estrogen loss as a potential factor. Estrogen holds a significant role in amyloid precursor protein (APP) processing and overall neuronal health through the regulation of brain-derived neurotrophic factor (BDNF), a factor that is also reduced in postmenopausal women. BDNF is a known contributor to neuronal health and its reduced expression is typically linked to AD disorders. Exercise is known to increase BDNF and may provide an accessible activity for postmenopausal women to reduce their risk of AD. This review aims to discuss the relationship between estrogen, exercise, and BDNF in AD pathology.

9Mechanisms of sex differences in Alzheimer's disease.PubMed

Chloe Lopez-Lee, Eileen Ruth S Torres, Gillian Carling, et al.
Neuron. 2024 Apr 17;112(8):1208-1221. doi: 10.1016/j.neuron.2024.01.024. Epub 2024 Feb 22.
Alzheimer's disease (AD) and the mechanisms underlying its etiology and progression are complex and multifactorial. The higher AD risk in women may serve as a clue to better understand these complicated processes. In this review, we examine aspects of AD that demonstrate sex-dependent effects and delve into the potential biological mechanisms responsible, compiling findings from advanced technologies such as single-cell RNA sequencing, metabolomics, and multi-omics analyses. We review evidence that sex hormones and sex chromosomes interact with various disease mechanisms during aging, encompassing inflammation, metabolism, and autophagy, leading to unique characteristics in disease progression between men and women.

10Sex Differences in Alzheimer's Disease.PubMed

Neelum T Aggarwal, Michelle M Mielke
Neurol Clin. 2023 May;41(2):343-358. doi: 10.1016/j.ncl.2023.01.001.
Reviewing the research presented in this article, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex and gender differences in Alzheimer's dementia (AD) are due to differences in longevity, survival bias, and comorbidities. Medical, genetic, psychosocial, and behavioral factors, in addition to hormonal factors, can differentially affect the risk and progression of AD in women versus men. Further, evaluation of sex differences in AD progression and the trajectory of change in cognitive function, neuroimaging, cerebrospinal fluid (CSF), and blood-based biomarkers of AD is needed. Finally, identifying sex differences in AD biomarkers and change across the lifespan is critical for the planning of prevention trials to reduce the risk of developing AD.

11Understanding the impact of sex and gender in Alzheimer's disease: A call to action.PubMed

Rebecca A Nebel, Neelum T Aggarwal, Lisa L Barnes, et al.
Alzheimers Dement. 2018 Sep;14(9):1171-1183. doi: 10.1016/j.jalz.2018.04.008. Epub 2018 Jun 12.
INTRODUCTION: Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, and management of Alzheimer's disease (AD) dementia. However, sex and gender have not yet been adequately integrated into many of these approaches. METHODS: The Society for Women's Health Research Interdisciplinary Network on AD, comprised of an expert panel of scientists and clinicians, reviewed ongoing and published research related to sex and gender differences in AD. RESULTS: The current review is a result of this Network's efforts and aims to: (1) highlight the current state-of-the-science in the AD field on sex and gender differences; (2) address knowledge gaps in assessing sex and gender differences; and (3) discuss 12 priority areas that merit further research. DISCUSSION: The exclusion of sex and gender has impeded faster advancement in the detection, treatment, and care of AD across the clinical spectrum. Greater attention to these differences will improve outcomes for both sexes.

12Estrogen Signaling in Alzheimer's Disease: Molecular Insights and Therapeutic Targets for Alzheimer's Dementia.PubMed

Md Sahab Uddin, Md Motiar Rahman, Md Jakaria, et al.
Mol Neurobiol. 2020 Jun;57(6):2654-2670. doi: 10.1007/s12035-020-01911-8. Epub 2020 Apr 15.
Estrogens play a crucial physiological function in the brain; however, debates exist concerning the role of estrogens in Alzheimer's disease (AD). Women during pre-, peri-, or menopause periods are more susceptible for developing AD, suggesting the connection of sex factors and a decreased estrogen signaling in AD pathogenesis. Yet, the underlying mechanism of estrogen-mediated neuroprotection is unclarified and is complicated by the existence of estrogen-related factors. Consequently, a deeper analysis of estrogen receptor (ER) expression and estrogen-metabolizing enzymes could interpret the importance of estrogen in age-linked cognitive alterations. Previous studies propose that hormone replacement therapy may attenuate AD onset in postmenopausal women, demonstrating that estrogen signaling is important for the development and progression of AD. For example, ERα exerts neuroprotection against AD by maintaining intracellular signaling cascades and study reported reduced expression of ERα in hippocampal neurons of AD patients. Similarly, reduced expression of ERβ in female AD patients has been associated with abnormal function in mitochondria and improved markers of oxidative stress. In this review, we discuss the critical interaction between estrogen signaling and AD. Moreover, we highlight the potential of targeting estrogen-related signaling for therapeutic intervention in AD.

13Gender, sex steroid hormones, and Alzheimer's disease.PubMed

Rebekah S Vest, Christian J Pike
Horm Behav. 2013 Feb;63(2):301-7. doi: 10.1016/j.yhbeh.2012.04.006. Epub 2012 Apr 19.
Age-related loss of sex steroid hormones is a established risk factor for the development of Alzheimer's disease (AD) in women and men. While the relationships between the sex steroid hormones and AD are not fully understood, findings from both human and experimental paradigms indicate that depletion of estrogens in women and androgens in men increases vulnerability of the aging brain to AD pathogenesis. We review evidence of a wide range of beneficial neural actions of sex steroid hormones that may contribute to their hypothesized protective roles against AD. Both estrogens and androgens exert general neuroprotective actions relevant to a several neurodegenerative conditions, some in a sex-specific manner, including protection from neuron death and promotion of select aspects of neural plasticity. In addition, estrogens and androgens regulate key processes implicated in AD pathogenesis, in particular the accumulation of β-amyloid protein. We discuss evidence of hormone-specific mechanisms related to the regulation of the production and clearance of β-amyloid as critical protective pathways. Continued elucidation of these pathways promises to yield effective hormone-based strategies to delay development of AD.

14The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.PubMed

Xinyi Wang, Shu Feng, Qianting Deng, et al.
Mol Cell Biochem. 2025 Apr;480(4):1983-1998. doi: 10.1007/s11010-024-05071-4. Epub 2024 Aug 1.
Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

15The interplay between age at menopause and synaptic integrity on Alzheimer's disease risk in women.PubMed

Madeline Wood Alexander, William G Honer, Rowan Saloner, et al.
Sci Adv. 2025 Mar 7;11(10):eadt0757. doi: 10.1126/sciadv.adt0757. Epub 2025 Mar 5.
Menopause is a major biological transition that may influence women's late-life brain health. Earlier estrogen depletion-via earlier menopause-has been associated with increased risk for Alzheimer's disease (AD). Synaptic dysfunction also incites and exacerbates AD progression. We investigated whether age at menopause and synaptic health together influence AD neuropathology and cognitive trajectories using clinical and autopsy data from 268 female decedents in the Rush Memory and Aging Project. We observed significant interactions between age at menopause and synaptic integrity on cognitive decline and tau tangles, such that earlier menopause strengthened the associations of reduced synaptic integrity with faster cognitive decline and elevated tau. Exploratory analyses showed that these relationships were attenuated in women who took menopausal hormone therapy. These findings suggest that midlife endocrine processes or their sequalae may influence synaptic vulnerability to AD. Interventions addressing both hormonal factors and synaptic health could enhance resilience to dementia in women.

16Sex differences in Alzheimer disease - the gateway to precision medicine.PubMed

Maria Teresa Ferretti, Maria Florencia Iulita, Enrica Cavedo, et al.
Nat Rev Neurol. 2018 Aug;14(8):457-469. doi: 10.1038/s41582-018-0032-9.
Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment.

17The Epidemiology of Alzheimer's Disease Modifiable Risk Factors and Prevention.PubMed

X-X Zhang, Y Tian, Z-T Wang, et al.
J Prev Alzheimers Dis. 2021;8(3):313-321. doi: 10.14283/jpad.2021.15.
Mild Alzheimer's disease is the leading cause of dementia, accounting for 50-70% of cases. Alzheimer's disease is an irreversible neurodegenerative disease, which affects daily life activities and social functioning. As life expectancy increases and demographic ageing occurs, the global prevalence of Alzheimer's disease is expected to continue to rise especially in developing countries, leading to a costly burden of disease. Alzheimer's disease is a complex and multifactorial disorder that is determined by the interaction of genetic susceptibility and environmental factors across the life course. Epidemiological studies have identified potential modifiable risk and protective factors for Alzheimer's disease prevention. Moreover, Alzheimer's disease is considered to start decades earlier before clinical symptoms occur, thus interventions targeting several risk factors in non-demented elderly people even middle-aged population might prevent or delay Alzheimer's disease onset. Here, we provide an overview of current epidemiological advances related to Alzheimer's disease modifiable risk factors, highlighting the concept of early prevention.

18Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.PubMed

Jin-Tai Yu, Wei Xu, Chen-Chen Tan, et al.
J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20.
BACKGROUND: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS: A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

19Is Alzheimer's Disease Risk Modifiable?PubMed

Alberto Serrano-Pozo, John H Growdon
J Alzheimers Dis. 2019;67(3):795-819. doi: 10.3233/JAD181028.
Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed, especially Alzheimer's disease (AD) and cerebrovascular ischemic disease (CVID), rather than pure AD. While these could be just two frequent unrelated comorbidities in the elderly, epidemiological research has reinforced the idea that mid-life (age <65 years) vascular risk factors increase the risk of late-onset (age ≥ 65 years) dementia, and specifically AD. By contrast, healthy lifestyle choices such as leisure activities, physical exercise, and Mediterranean diet are considered protective against AD. Remarkably, several large population-based longitudinal epidemiological studies have recently indicated that the incidence and prevalence of dementia might be decreasing in Western countries. Although it remains unclear whether these positive trends are attributable to neuropathologically definite AD versus CVID, based on these epidemiological data it has been estimated that a sizable proportion of AD cases could be preventable. In this review, we discuss the current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies, and analyze the opportunities for therapeutic and preventative interventions.

20Meta-analysis of modifiable risk factors for Alzheimer's disease.PubMed

Wei Xu, Lan Tan, Hui-Fu Wang, et al.
J Neurol Neurosurg Psychiatry. 2015 Dec;86(12):1299-306. doi: 10.1136/jnnp-2015-310548. Epub 2015 Aug 20.
BACKGROUND: The aetiology of Alzheimer's disease (AD) is believed to involve environmental exposure and genetic susceptibility. The aim of our present systematic review and meta-analysis was to roundly evaluate the association between AD and its modifiable risk factors. METHODS: We systematically searched PubMed and the Cochrane Database of Systematic Reviews from inception to July 2014, and the references of retrieved relevant articles. We included prospective cohort studies and retrospective case-control studies. RESULTS: 16,906 articles were identified of which 323 with 93 factors met the inclusion criteria for meta-analysis. Among factors with relatively strong evidence (pooled population >5000) in our meta-analysis, we found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD. We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD. We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreasing the risk) in influencing AD risk. We identified no evidence suggestive of significant association with occupational exposures. CONCLUSIONS: Effective interventions in diet, medications, biochemical exposures, psychological condition, pre-existing disease and lifestyle may decrease new incidence of AD.

21Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis.PubMed

David C Perry, Virginia E Sturm, Matthew J Peterson, et al.
J Neurosurg. 2016 Feb;124(2):511-26. doi: 10.3171/2015.2.JNS14503. Epub 2015 Aug 28.
OBJECTIVE: Mild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimer's disease, Parkinson's disease, depression, and other illnesses. This study's objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease. METHODS: All studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics. RESULTS: Fifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44-1.93, p < 0.0001). Prior TBI was independently associated with both neurological (OR 1.55, 95% CI 1.31-1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI 1.50-2.66, p < 0.0001) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimer's disease, Parkinson's disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI. CONCLUSIONS: History of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.

22Traumatic Brain Injury and Risk of Alzheimer's Disease and Related Dementias in the Population.PubMed

Michelle M Mielke, Jeanine E Ransom, Jay Mandrekar, et al.
J Alzheimers Dis. 2022;88(3):1049-1059. doi: 10.3233/JAD-220159.
BACKGROUND: Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer's disease and related dementias (ADRD) have yielded conflicting results, which may be due to methodological differences. OBJECTIVE: To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD. METHODS: All TBI events among Olmsted County, Minnesota residents aged > 40 years from 1985-1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD. RESULTS: A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02-1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18). CONCLUSION: Our analyses support including TBI as a potential risk factor for developing ADRD.

23Mild Traumatic Brain Injuries and Future Risk of Developing Alzheimer's Disease: Systematic Review and Meta-Analysis.PubMed

Alicia Graham, Gill Livingston, Lucy Purnell, et al.
J Alzheimers Dis. 2022;87(3):969-979. doi: 10.3233/JAD-220069.
BACKGROUND: Traumatic brain injury (TBI) increases the risk of future dementia and Alzheimer's disease (AD). However, it is unclear whether this is true for mild TBI (mTBI). OBJECTIVE: To explore the association between mTBI and subsequent risk of developing AD. METHOD: We systematically searched four electronic databases from January 1954 to April 2020. We included studies reporting primary data and where mTBI preceded AD by≥5 years. We meta-analyzed included studies for both high quality studies and studies with a follow up of > 10 years. RESULT: We included 5 of the 10,435 results found. Meta-analysis found a history of mTBI increased risk of AD (pooled relative risk = 1.18, 95% CI 1.11-1.25, N = 3,149,740). The sensitivity analysis including only studies in which mTBI preceded AD by > 10 years, excluded two very large studies and resulted in wider confidence intervals (RR = 2.02, 95% CI 0.66-6.21, N = 2307). CONCLUSION: There is an increased risk of AD following mTBI. Our findings of increased risk even with mTBI means it cannot be assumed that mild head injuries from sports are harmless. The sensitivity analysis suggests that we cannot exclude reverse causation, and longer follow up times are needed. Implementation of policy to reduce mTBIs, including in children and sportsmen, are urgently needed. Further research is needed on the effect of frequency and age at injury of mTBIs.

24Viruses and neurodegeneration.PubMed

Li Zhou, Monica Miranda-Saksena, Nitin K Saksena
Virol J. 2013 May 31;10:172. doi: 10.1186/1743-422X-10-172.
Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non-viral-induced neurodegenerative diseases in humans, as they are well described in literature.Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non-viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration.

25Neurodegenerative and Neurodevelopmental Diseases and the Gut-Brain Axis: The Potential of Therapeutic Targeting of the Microbiome.PubMed

Brian Bicknell, Ann Liebert, Thomas Borody, et al.
Int J Mol Sci. 2023 May 31;24(11):9577. doi: 10.3390/ijms24119577.
The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases. This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.

26SARS-CoV-2 and neurodegenerative diseases: what we know and what we don't.PubMed

Paul Lingor, Antonia F Demleitner, Andreas W Wolff, et al.
J Neural Transm (Vienna). 2022 Sep;129(9):1155-1167. doi: 10.1007/s00702-022-02500-w. Epub 2022 Apr 17.
Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field.

27Alzheimer's Disease: Pathogenesis and Therapeutic Interventions.PubMed

John O Ogbodo, Chinazom P Agbo, Ugochi O Njoku, et al.
Curr Aging Sci. 2022;15(1):2-25. doi: 10.2174/1874609814666210302085232.
BACKGROUND: Alzheimer's Disease (AD) is the most common cause of dementia. Genetics, excessive exposure to environmental pollutants, as well as unhealthy lifestyle practices are often linked to the development of AD. No therapeutic approach has achieved complete success in treating AD; however, early detection and management with appropriate drugs are key to improving prognosis. INTERVENTIONS: The pathogenesis of AD was extensively discussed in order to understand the reasons for the interventions suggested. The interventions reviewed include the use of different therapeutic agents and approaches, gene therapy, adherence to healthy dietary plans (Mediterranean diet, Okinawan diet and MIND diet), as well as the use of medicinal plants. The potential of nanotechnology as a multidisciplinary and interdisciplinary approach in the design of nano-formulations of AD drugs and the use of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as theranostic tools for early detection of Alzheimer's disease were also discussed.

28Environmental toxins and Alzheimer's disease progression.PubMed

Maryam Vasefi, Ehsan Ghaboolian-Zare, Hamzah Abedelwahab, et al.
Neurochem Int. 2020 Dec;141:104852. doi: 10.1016/j.neuint.2020.104852. Epub 2020 Sep 30.
Alzheimer's disease (AD) is the most common form of dementia, which causes progressive memory loss and cognitive decline. Effective strategies to treat or prevent remains one of the most challenging undertakings in the medical field. AD is a complex and multifactorial disease that involves several risk factors. Aging and genetic factors both play important roles in the onset of the AD, however; certain environmental factors have been reported to increase the risk of AD. Chronic exposure to toxins has been seen as an environmental factor that may increase the risk of developing a neurodegenerative disease such as AD. Exposure to metals and biotoxins produced by bacteria, molds, and viruses may contribute to the cognitive decline and pathophysiology associated with AD. Toxins may contribute to the pathology of the disease through various mechanisms such as deposition of amyloid-beta (Aβ) plaques and tangles in the brain, induction of apoptosis, inflammation, or oxidative damage. Here, we will review how toxins affect brain physiology with a focus on mechanisms by which toxins may contribute to the development and progression of AD. A better understanding of these mechanisms may help contribute towards the development of an effective strategy to slow the progression of AD.

29[Environmental pollutants and Alzheimer's disease].PubMed

Bao Guo, Qian Ba
Sheng Li Xue Bao. 2023 Dec 25;75(6):740-766.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. The main hypotheses about the pathogenesis of AD include the hypothesis of β-amyloid protein, the hypothesis of abnormal phosphorylation of Tau protein, and the hypothesis of neuroinflammation. In recent years, environmental pollutants have been considered as an important factor in causing neurological dysfunction. Common environmental pollutants include heavy metals, pesticides, polychlorinated biphenyls, microplastics, and air pollutants, all of which have been proven to have neurotoxicity. In this review, we not only discussed epidemiological and animal experimental studies that link environmental pollution with AD, but also summarized the mechanisms of action of relevant toxins, providing insights for studying the interrelationships between environmental pollutants and AD.

30Exercise and dementia prevention.PubMed

Jane Alty, Maree Farrow, Katherine Lawler
Pract Neurol. 2020 May;20(3):234-240. doi: 10.1136/practneurol-2019-002335. Epub 2020 Jan 21.
Ageing, genetic, medical and lifestyle factors contribute to the risk of Alzheimer's disease and other dementias. Around a third of dementia cases are attributable to modifiable risk factors such as physical inactivity, smoking and hypertension. With the rising prevalence and lack of neuroprotective drugs, there is renewed focus on dementia prevention strategies across the lifespan. Neurologists encounter many people with risk factors for dementia and are frequently asked whether lifestyle changes may help. Exercise has emerged as a key intervention for influencing cognition positively, including reducing the risk of age-related cognitive decline and dementia. This article focuses on the current evidence for physical inactivity as a modifiable dementia risk factor and aims to support neurologists when discussing risk reduction.

31Physical exercise in the prevention and treatment of Alzheimer's disease.PubMed

Adrian De la Rosa, Gloria Olaso-Gonzalez, Coralie Arc-Chagnaud, et al.
J Sport Health Sci. 2020 Sep;9(5):394-404. doi: 10.1016/j.jshs.2020.01.004. Epub 2020 Feb 4.
Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written over the ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid β turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations.

32Role of diet and exercise in aging, Alzheimer's disease, and other chronic diseases.PubMed

Sachi Khemka, Aananya Reddy, Ricardo Isaiah Garcia, et al.
Ageing Res Rev. 2023 Nov;91:102091. doi: 10.1016/j.arr.2023.102091. Epub 2023 Oct 11.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. Genetic mutations cause a small proportion (1-2%) of early-onset AD, with mutations in amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Major contributing factors of late-onset AD are ApoE4 genotype, traumatic brain injury, diabetes, obesity, hypertension, cardiovascular conditions, in addition to lifestyle factors, such as unhealthy diet and lack of physical exercise. Disease progression can be delayed and/or prevented to a greater extent by adopting healthy lifestyle with balanced and antioxidant enriched diet and daily exercise. The interaction and interplay of diet, exercise, age, and pharmacological interventions holds a crucial role in the progression, pathogenesis and management of AD and its comorbidities, including diabetes, obesity, hypertension and cardiovascular conditions. Antioxidant enriched diet contributes to brain health, glucose control, weight management, and cardiovascular well-being. Regular exercise removes toxins including free radicals and enhances insulin sensitivity, and supports cardiovascular function. In the current article, we discussed, the role of diet, and exercise in aging, AD and other conditions including diabetes, obesity, hypertension, cardiovascular conditions. This article also highlights the impact of medication, socioeconomic and lifestyle factors, and pharmacological interventions. These aspects were discussed in different races and ethnic groups in Texas, and the US.

33Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: a randomized, controlled clinical trial.PubMed

Dean Ornish, Catherine Madison, Miia Kivipelto, et al.
Alzheimers Res Ther. 2024 Jun 7;16(1):122. doi: 10.1186/s13195-024-01482-z.
BACKGROUND: Evidence links lifestyle factors with Alzheimer's disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD. METHODS: A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer's Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher's exact test. Secondary outcomes included plasma Aβ42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures. RESULTS: Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aβ42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC (p= 0.001), CDR-SB (p= 0.032), and CDR Global (p= 0.037) tests and borderline significance in the ADAS-Cog test (p= 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aβ42/40 ratio increased in the intervention group and decreased in the control group (p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aβ42/40 ratio. The microbiome improved only in the intervention group (p <0.0001). CONCLUSIONS: Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD. TRIAL REGISTRATION: Approved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

34Dementia Prevention and Treatment: A Narrative Review.PubMed

David B Reuben, Sarah Kremen, Donovan T Maust
JAMA Intern Med. 2024 May 1;184(5):563-572. doi: 10.1001/jamainternmed.2023.8522.
IMPORTANCE: Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance. OBSERVATIONS: Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future. CONCLUSIONS AND RELEVANCE: Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.

35Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease.PubMed

Miia Kivipelto, Francesca Mangialasche, Tiia Ngandu
Nat Rev Neurol. 2018 Nov;14(11):653-666. doi: 10.1038/s41582-018-0070-3.
Research into dementia prevention is of paramount importance if the dementia epidemic is to be halted. Observational studies have identified several potentially modifiable risk factors for dementia, including hypertension, dyslipidaemia and obesity at midlife, diabetes mellitus, smoking, physical inactivity, depression and low levels of education. Randomized clinical trials are needed that investigate whether interventions targeting these risk factors can reduce the risk of cognitive decline and dementia in elderly adults, but such trials are methodologically challenging. To date, most preventive interventions have been tested in small groups, have focused on a single lifestyle factor and have yielded negative or modest results. Given the multifactorial aetiology of dementia and late-onset Alzheimer disease, multidomain interventions that target several risk factors and mechanisms simultaneously might be necessary for an optimal preventive effect. In the past few years, three large multidomain trials (FINGER, MAPT and PreDIVA) have been completed. The FINGER trial showed that a multidomain lifestyle intervention can benefit cognition in elderly people with an elevated risk of dementia. The primary results from the other trials did not show a statistically significant benefit of preventive interventions, but additional analyses among participants at risk of dementia showed beneficial effects of intervention. Overall, results from these three trials suggest that targeting of preventive interventions to at-risk individuals is an effective strategy. This Review discusses the current knowledge of lifestyle-related risk factors and results from novel trials aiming to prevent cognitive decline and dementia. Global initiatives are presented, including the World Wide FINGERS network, which aims to harmonize studies on dementia prevention, generate high-quality scientific evidence and promote its implementation.

36Multisystem failure, tipping points, and risk of Alzheimer's disease.PubMed

Simona Merlini, Edward J Bedrick, Roberta Diaz Brinton, et al.
Alzheimers Dement. 2025 May;21(5):e70249. doi: 10.1002/alz.70249.
INTRODUCTION: Medical conditions including obesity, diabetes, hyperlipidemia, and depression significantly increased risk of Alzheimer's disease (AD). However, effect of their duration, influenced by non-modifiable factors like chromosomal sex and apolipoprotein E (APOE) genotype, remains unclear. METHODS: Data from 5644 UKBiobank participants were analyzed using Cox regression model to identify critical tipping points based on age of onset, risk factor (RF) duration and their interaction with sex and APOE genotype. RESULTS: Hypertension or diabetes before age 62 exerted greater AD risk than APOEε4 alone. Obesity before age 62 increased AD risk by 54%, with the risk nearly tripling between ages 62-72. Hyperlipidemia and depression were associated with age-independent risk increases of 33% and 69%, respectively. After age 72, APOEε4 became the dominant RF. DISCUSSION: Duration of AD-risk-factors can have a greater impact than APOEε4. Identification of critical age-related tipping points highlights temporal dynamics of AD progression and role of multisystem failure in AD progression. HIGHLIGHTS: AD risk factors impact AD onset, especially diagnosed between ages 62 and 72. Later diagnoses of hypertension, diabetes, and obesity delayed AD onset. Hyperlipidemia and depression increased AD risk by 33% and 69%, age-independent. APOEε4 carriers regardless of sex exhibited a higher risk increasing with age. Trajectories differed between APOEε4 carriers and non-carriers across sex.

37Synergistic interaction between APOE and family history of Alzheimer's disease on cerebral amyloid deposition and glucose metabolism.PubMed

Dahyun Yi, Younghwa Lee, Min Soo Byun, et al.
Alzheimers Res Ther. 2018 Aug 23;10(1):84. doi: 10.1186/s13195-018-0411-x.
BACKGROUND: Recently, the field of gene-gene or gene-environment interaction research appears to have gained growing interest, although it is seldom investigated in Alzheimer's disease (AD). Hence, the current study aims to investigate interaction effects of the key genetic and environmental risks-the apolipoprotein ε4 allele (APOE4) and family history of late-onset AD (FH)-on AD-related brain changes in cognitively normal (CN) middle-aged and older adults. METHODS: [C] Pittsburg compound-B (PiB) positron emission tomography (PET) imaging as well as [F] fluoro-2-deoxyglucose (FDG) PET that were simultaneously taken with T1-weighted magnetic resonance imaging (MRI) were obtained from 268 CNs from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE). Composite standardized uptake value ratios were obtained from PiB-PET and FDG-PET images in the AD signature regions of interests (ROIs) and analyzed. Voxel-wise analyses were also performed to examine detailed regional changes not captured by the ROI analyses. RESULTS: A significant synergistic interaction effect was found between the APOE4 and FH on amyloid-beta (Aβ) deposition in the AD signature ROIs as well as other regions. Synergistic interaction effects on cerebral glucose metabolism were observed in the regions not captured by the AD signature ROIs, particularly in the medial temporal regions. CONCLUSIONS: Strong synergistic effects of APOE4 and FH on Aβ deposition and cerebral glucose metabolism in CN adults indicate possible gene-to-gene or gene-to-environment interactions that are crucial for pathogenesis of AD involving Aβ. Other unspecified risk factors-genes and/or environmental-that are captured by the positive FH status might either coexpress or interact with APOE4 to alter AD-related brain changes in CN. Healthy people with both FH and APOE4 need more attention for AD prevention.

38ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations.PubMed

Bilcag Akgun, Alexander V Gulyayev, Motunrayo Coker, et al.
Alzheimers Dement. 2025 Aug;21(8):e70583. doi: 10.1002/alz.70583.
INTRODUCTION: Apolipoprotein E (APOE) and ABCA7 genes are among the strongest heritable risk factors for Alzheimer's disease (AD) in African-ancestry (AA) populations. APOE 𝜀4 affects both risk and age at onset (AAO), with lower risk in AA populations. This study evaluates the independent and interactive effects of the AA-specific ABCA7 frameshift deletion and APOE 𝜀4 allele on AAO. METHODS: We analyzed 3510 AA individuals, including AD cases and controls. Cox regression models assessed the effects of ABCA7 deletion, APOE genotypes, and their interactive influence on AAO. RESULTS: APOE ε3/ε4 carriers with the ABCA7 deletion had a significantly shorter survival compared to ε3/ε4 carriers without the deletion. No significant differences were found between deletion carriers and non-carriers with APOE ε3/ε3 or ε4/ε4 genotypes. DISCUSSION: Our study showed that the ABCA7 deletion lowered the AAO of AD in APOE ε3/ε4 carriers from AA populations. These findings suggest that the AA-specific ABCA7 deletion and the APOE ε4 allele have synergistic effects on AAO. HIGHLIGHTS: AA-specific ABCA7 deletion lowers AAO of AD in APOE ε3/ε4 carriers from AA populations. Findings suggest an interaction between ABCA7 deletion and APOE ε4 on AAO. APOE ε4 has a strong, dose-dependent effect on AAO of AD in AA individuals. ABCA7 deletion impact on AAO of AD is stronger in females with APOE ε3/ε4.

39Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk.PubMed

Eloy Rodríguez-Rodríguez, Ignacio Mateo, Jon Infante, et al.
Brain Res. 2009 Jul 14;1280:166-71. doi: 10.1016/j.brainres.2009.05.019. Epub 2009 May 14.
A number of studies suggest that increased cellular cholesterol levels induce high amyloid beta (Abeta) production, which is central to the pathogenesis of Alzheimer's disease (AD). In the brain, glial cells have hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) as the major rate-limiting enzyme in the novo synthesis of cholesterol, which once synthesized, is secreted via the cholesterol transporter ABCA1. Overexpression of HMGCR in concert with underexpression of ABCA1 would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined two HMGCR polymorphisms located in 5'-UTR (rs3931914) and promoter (-911, rs3761740) regions of the gene, and two ABCA1 polymorphisms (-14, rs1800977; and -477, rs2422493) located in promoter region of the gene, in a group of 325 Spanish AD patients and 383 controls. Subjects carrying both the HMGCR (5'-UTR) GG genotype and the ABCA1 (-14) TT genotype (adjusted by age, sex and APOE status OR=2.77; 95% CI=1.16-6.61; p=0.02), or the ABCA1 (-477) TT genotype (adjusted by age, sex and APOE status OR=2.07; 95% CI=1.14-3.78; p=0.02) had a higher risk of developing AD than subjects without these risk genotypes, and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes may help in determining the risk profile for AD.

40APOE ε4 carriers share immune-related proteomic changes across neurodegenerative diseases.PubMed

Artur Shvetcov, Erik C B Johnson, Laura M Winchester, et al.
Nat Med. 2025 Aug;31(8):2590-2601. doi: 10.1038/s41591-025-03835-z. Epub 2025 Jul 15.
The APOE ε4 genetic variant is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is increasingly being implicated in other neurodegenerative diseases. Using the Global Neurodegeneration Proteomics Consortium SomaScan dataset covering 1,346 cerebrospinal fluid (CSF) and 9,924 plasma samples, we used machine learning-based proteome profiling to identify an APOE ε4 proteomic signature shared across individuals with AD, frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and nonimpaired controls. This signature was enriched in pro-inflammatory immune and infection pathways as well as immune cells, including monocytes, T cells and natural killer cells. Analysis of the dorsolateral prefrontal cortex proteome for 262 donors from the Accelerating Medicines Partnership for AD UPenn Proteomics Study revealed a consistent APOE ε4 phenotype, independent of neurodegenerative pathology, including amyloid-β tau and gliosis for all diseases, as well as TDP-43 in ALS and FTD cases, and α-synuclein in PD and PDD cases. While systemic proteomic changes were consistent across APOE ε4 carriers, their relationship with clinical and lifestyle factors, such as hypertension and smoking, varied by disease. These findings suggest APOE ε4 confers a systemic biological vulnerability that is necessary but not sufficient for neurodegeneration, emphasizing the need to consider gene-environment interactions. Overall, our study reveals a conserved APOE ε4-associated pro-inflammatory immune signature persistent across the brain, CSF and plasma irrespective of neurodegenerative disease, highlighting a fundamental, disease-independent biological vulnerability to neurodegeneration. This work reframes APOE ε4 as a pleiotropic immune modulator rather than an AD-specific risk gene, providing a foundation for precision biomarker development and early intervention strategies across neurodegenerative diseases.

41Working memory and executive function decline across normal aging, mild cognitive impairment, and Alzheimer's disease.PubMed

Anna-Mariya Kirova, Rebecca B Bays, Sarita Lagalwar
Biomed Res Int. 2015;2015:748212. doi: 10.1155/2015/748212. Epub 2015 Oct 15.
Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by deficits in episodic memory, working memory (WM), and executive function. Examples of executive dysfunction in AD include poor selective and divided attention, failed inhibition of interfering stimuli, and poor manipulation skills. Although episodic deficits during disease progression have been widely studied and are the benchmark of a probable AD diagnosis, more recent research has investigated WM and executive function decline during mild cognitive impairment (MCI), also referred to as the preclinical stage of AD. MCI is a critical period during which cognitive restructuring and neuroplasticity such as compensation still occur; therefore, cognitive therapies could have a beneficial effect on decreasing the likelihood of AD progression during MCI. Monitoring performance on working memory and executive function tasks to track cognitive function may signal progression from normal cognition to MCI to AD. The present review tracks WM decline through normal aging, MCI, and AD to highlight the behavioral and neurological differences that distinguish these three stages in an effort to guide future research on MCI diagnosis, cognitive therapy, and AD prevention.

42Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier.PubMed

Pushpa Tryphena Kamatham, Rashi Shukla, Dharmendra Kumar Khatri, et al.
Ageing Res Rev. 2024 Nov;101:102481. doi: 10.1016/j.arr.2024.102481. Epub 2024 Sep 3.
Alzheimer's disease (AD) is the most common cause of dementia and accounts for 60-70 % of all cases. It affects millions of people worldwide. AD poses a substantial economic burden on societies and healthcare systems. AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. As the prevalence of AD continues to increase, understanding its pathogenesis, improving diagnostic methods, and developing effective therapeutics have become paramount. This comprehensive review delves into the intricate mechanisms underlying AD, explores the current state of diagnostic techniques, and examines emerging therapeutic strategies. By revealing the complexities of AD, this review aims to contribute to the growing body of knowledge surrounding this devastating disease.

43Connected speech and language in mild cognitive impairment and Alzheimer's disease: A review of picture description tasks.PubMed

Kimberly D Mueller, Bruce Hermann, Jonilda Mecollari, et al.
J Clin Exp Neuropsychol. 2018 Nov;40(9):917-939. doi: 10.1080/13803395.2018.1446513. Epub 2018 Apr 19.
INTRODUCTION: The neuropsychological profile of people with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia includes a history of decline in memory and other cognitive domains, including language. While language impairments have been well described in AD dementia, language features of MCI are less well understood. Connected speech and language analysis is the study of an individual's spoken discourse, usually elicited by a target stimulus, the results of which can facilitate understanding of how language deficits typical of MCI and AD dementia manifest in everyday communication. Among discourse genres, picture description is a constrained task that relies less on episodic memory and more on semantic knowledge and retrieval, within the cognitive demands of a communication context. Understanding the breadth of evidence across the continuum of cognitive decline will help to elucidate the areas of strength and need in terms of using this method as an evaluative tool for both cognitive changes and everyday functional communication. METHOD: We performed an extensive literature search of peer-reviewed journal articles that focused on the use of picture description tasks for evaluating language in persons with MCI or AD dementia. We selected articles based on inclusion and exclusion criteria and described the measures assessed, the psychometric properties that were reported, the findings, and the limitations of the included studies. RESULTS: 36 studies were selected and reviewed. Across all 36 studies, there were 1, 127 patients with AD dementia and 274 with MCI or early cognitive decline. Multiple measures were examined, including those describing semantic content, syntactic complexity, speech fluency, vocal parameters, and pragmatic language. Discriminant validity widely reported and distinct differences in language were observable between adults with dementia and controls; fewer studies were able to distinguish language differences between typically aging adults and those with MCI. DISCUSSION: Our review shows that picture description tasks are useful tools for detecting differences in a wide variety of language and communicative measures. Future research should expand knowledge about subtle changes to language in preclinical AD and Mild Cognitive Impairment (MCI) which may improve the utility of this method as a clinically meaningful screening tool.

44Language dysfunction.PubMed

David J Gill, Krista M Damann
Continuum (Minneap Minn). 2015 Jun;21(3 Behavioral Neurology and Neuropsychiatry):627-45. doi: 10.1212/01.CON.0000466657.97531.af.
PURPOSE OF REVIEW: Language is a complex brain function requiring a number of cognitive processes and is commonly affected by both focal brain lesions and neurodegenerative disorders. This article reviews the neuroanatomic basis of language, assessment techniques of language function, and disorders affecting language. RECENT FINDINGS: Recent functional imaging studies of language suggest that the classic connectionist models of language function may be incomplete. These studies and those analyzing how the primary progressive aphasias (PPAs) affect language function suggest that language processing is completed through large-scale distributed networks. The use of structured, standardized techniques allows for the diagnosis of focal brain lesions affecting language function as well as neurodegenerative and psychogenic causes of language dysfunction. SUMMARY: By employing an accurate, neuroanatomically grounded language assessment technique, the neurologist can reach the correct diagnosis and implement the optimal management plan for patients with language disorders. Neurologists should also be aware of new information regarding the neural basis of language function as our understanding of the complex cognitive process of language continues to evolve.

45Aphasia(s) in Alzheimer.PubMed

M Teichmann, S Ferrieux
Rev Neurol (Paris). 2013 Oct;169(10):680-6. doi: 10.1016/j.neurol.2013.06.001. Epub 2013 Sep 12.
Language disorders of degenerative origin are frequently tied to Alzheimer disease (AD) the different variants of which can result in primary and secondary aphasia syndromes. More specifically, Alzheimer pathology can primarily erode frontal, temporal or parietal language cortices resulting in three genuine AD language variants which account for about 30% of primary degenerative aphasias. Likewise, it can spread from non-language to language cortices leading to secondary language disorders like in typical amnesic AD and in several atypical AD variants. This paper reviews the whole set of AD variants by characterising their impact on the neural language system and on linguistic functioning. It also provides cues for diagnostic strategies which are essential for linguistic, syndromic and nosological patient classification, for adequate clinical follow-up and for guiding language rehabilitation. Such diagnostic approaches, founded on detailed linguistic phenotyping while integrating anatomical and neuropathological findings, also represent a crucial issue for future drug trials targeting the physio-pathological processes in degenerative aphasias.

46Alzheimer's disease and language impairments: social intervention and medical treatment.PubMed

Blanka Klimova, Petra Maresova, Martin Valis, et al.
Clin Interv Aging. 2015 Aug 27;10:1401-7. doi: 10.2147/CIA.S89714. eCollection 2015.
Communication is very important for people to be successfully integrated into social environment and make and maintain relationship. Particularly, language difficulties lead to social exclusion of the people affected with Alzheimer's disease (AD) and contribute to a significant decrease in the quality of their life and also have a big impact on their family members who in most cases become their caregivers who need to communicate with their loved ones in order to meet their needs. Therefore, the goal of this study is to describe language impairments in the individual phases of AD and discuss their improvement with respect to AD on the basis of literature review. The authors of this article use traditional research methods in order to achieve the goal set mentioned earlier. First, a method of literature review of available sources describing language impairments in the individual phases of AD is exploited. Second, to show how informal caregivers and relevant drugs can successfully intervene in the improvement of these language impairments, a method of comparison of different research studies exploring such social intervention and medical treatment is used.

47Mild Cognitive Impairment.PubMed

Ronald C Petersen
Continuum (Minneap Minn). 2016 Apr;22(2 Dementia):404-18. doi: 10.1212/CON.0000000000000313.
PURPOSE OF REVIEW: As individuals age, the quality of cognitive function becomes an increasingly important topic. The concept of mild cognitive impairment (MCI) has evolved over the past 2 decades to represent a state of cognitive function between that seen in normal aging and dementia. As such, it is important for health care providers to be aware of the condition and place it in the appropriate clinical context. RECENT FINDINGS: Numerous international population-based studies have been conducted to document the frequency of MCI, estimating its prevalence to be between 15% and 20% in persons 60 years and older, making it a common condition encountered by clinicians. The annual rate in which MCI progresses to dementia varies between 8% and 15% per year, implying that it is an important condition to identify and treat. In those MCI cases destined to develop Alzheimer disease, biomarkers are emerging to help identify etiology and predict progression. However, not all MCI is due to Alzheimer disease, and identifying subtypes is important for possible treatment and counseling. If treatable causes are identified, the person with MCI might improve. SUMMARY: MCI is an important clinical entity to identify, and while uncertainties persist, clinicians need to be aware of its diagnostic features to enable them to counsel patients. MCI remains an active area of research as numerous randomized controlled trials are being conducted to develop effective treatments.

48Progress on early diagnosing Alzheimer's disease.PubMed

Yixin Chen, Murad Al-Nusaif, Song Li, et al.
Front Med. 2024 Jun;18(3):446-464. doi: 10.1007/s11684-023-1047-1. Epub 2024 May 21.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions. The disease follows a continuum, starting with preclinical stages, progressing to mild cognitive and behavioral impairment, ultimately leading to dementia. Early detection of AD is crucial for better diagnosis and more effective treatment. However, the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive, and mostly are still not able to detect early disease state. Consequently, there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD. Various non-cognitive manifestations, including behavioral abnormalities, sleep disturbances, sensory dysfunctions, and physical changes, have been observed in the preclinical AD stage before occurrence of notable cognitive decline. Recent research advances have identified several biofluid biomarkers as early indicators of AD. This review focuses on these non-cognitive changes and newly discovered biomarkers in AD, specifically addressing the preclinical stages of the disease. Furthermore, it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.

49Personality traits and behavioral and psychological symptoms in patients at an early stage of Alzheimer's disease.PubMed

Cornelia Pocnet, Jérôme Rossier, Jean-Philippe Antonietti, et al.
Int J Geriatr Psychiatry. 2013 Mar;28(3):276-83. doi: 10.1002/gps.3822. Epub 2012 May 2.
OBJECTIVE: The origins of behavioral and psychological symptoms (BPS) in Alzheimer's disease (AD) are still poorly understood. Focusing on individual personality structure, we explored the relationship between premorbid personality and its changes over 5 years, and BPS in patients at an early stage of AD. METHOD: A total of 54 patients at an early stage of AD according to ICD-10 and NINCDS-ADRDA criteria and 64 control subjects were included. Family members filled in the Neuropsychiatric Inventory Questionnaire to evaluate their proxies' current BPS and the NEO Personality Inventory Revised twice, the first time to evaluate the participants' current personality and the second time to assess personality traits as they were remembered to be 5 years earlier. RESULTS: Behavioral and psychological symptoms, in particular apathy, depression, anxiety, and agitation, are frequent occurrences in early stage AD. Premorbid personality differed between AD patients and normal control, but it was not predictive of BPS in patients with AD. Personality traits clearly change in the course of beginning AD, and this change seems to develop in parallel with BPS as early signs of AD. CONCLUSIONS: Premorbid personality was not associated with BPS in early stage of AD, although complex and non-linear relationships between the two are not excluded. However, both personality and behavioral changes occur early in the course of AD, and recognizing them as possible, early warning signs of neurodegeneration may prove to be a key factor for early detection and intervention.

50Brain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer's Disease.PubMed

M Clara Selles, Mauricio M Oliveira, Sergio T Ferreira
J Alzheimers Dis. 2018;64(s1):S313-S327. doi: 10.3233/JAD-179925.
Alzheimer's disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver's health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets.

51Aging-associated sensory decline and Alzheimer's disease.PubMed

Suji Hong, Seung-Hyun Baek, Mitchell K P Lai, et al.
Mol Neurodegener. 2024 Dec 4;19(1):93. doi: 10.1186/s13024-024-00776-y.
Multisensory decline is common as people age, and aging is the primary risk of Alzheimer's Disease (AD). Recent studies have begun to shed light on the possibility that age-related sensory decline could accelerate AD pathogenesis, or be a prodromal indicator of AD. Sensory impairments, specifically in taste and smell, often emerge before cognitive symptoms in AD, indicating their potential as early biomarkers. Olfactory dysfunction has been frequently associated with AD and may offer valuable insights into early detection. Hearing impairment is significantly associated with AD, but its causal impact on AD progression remains unclear. The review also discusses visual and tactile deficits in AD, including retinal thinning and changes in tactile perception, highlighting their links to disease progression. Focusing on molecular mechanisms, the review explores the roles of amyloid-β (Aβ) accumulation and tau protein pathology in sensory decline and their bidirectional relationship with AD. In summary, the evidence presented conclusively supports advocating for an integrated approach to understanding AD and sensory decline, to enhance early detection, implementing preventive strategies, and developing therapeutic interventions for AD. This approach underscores the significance of sensory health in addressing neurodegenerative diseases, particularly AD.

52Early detection of Alzheimer's disease using the MEMORIES mnemonic.PubMed

Valentinus Besin, Farizky M Humardani
Chronic Dis Transl Med. 2024 Sep 3;11(1):22-32. doi: 10.1002/cdt3.150. eCollection 2025 Mar.
The rising incidence and death rates linked to Alzheimer's disease (AD) highlight an urgent issue. Genetic screening is celebrated as a significant advancement for its early detection capabilities, pinpointing those at risk before the emergence of symptoms. Yet, the limited availability of these technologies highlights a critical gap in widespread application. This review pivots to the potential of presymptomatic clinical assessments as a readily available, economical, and simple strategy for early detection. Traditionally, AD diagnosis relies on the late-stage identification of cognitive deterioration, functional impairments, and neuropsychiatric symptoms, coinciding with advanced brain degeneration. Conversely, emerging research identifies early indicators preceding significant degeneration, manifesting years before clinical symptoms. We introduce a mnemonic, MEMORIES, to categorize these prodromal: Metabolism changes, Eye/visual impairments, March (refer to gait disturbances), Olfactory dysfunction, Rhythm (blood pressure and heart rate), Insensitivity of the tongue, Ears (hearing loss), and Stool alterations. Recognizing these prodromal through clinical examinations provides a valuable strategy for initiating preventative actions against brain degeneration. This approach advocates for broadening the screening lens beyond genetic screening to encompass clinical evaluations, enhancing early detection and intervention opportunities for AD.

53Potential neural substrates underlying circadian and olfactory disruptions in preclinical Alzheimer's disease.PubMed

Quiana L Jeffs, Jonathan F Prather, William D Todd
Front Neurosci. 2023 Nov 29;17:1295998. doi: 10.3389/fnins.2023.1295998. eCollection 2023.
Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.

54Olfactory dysfunction as potential biomarker in neurodegenerative diseases: a narrative review.PubMed

Nicolas De Cleene, Katarína Schwarzová, Samuel Labrecque, et al.
Front Neurosci. 2025 Jan 7;18:1505029. doi: 10.3389/fnins.2024.1505029. eCollection 2024.
Neurodegenerative diseases represent a group of disorders characterized by progressive degeneration of neurons in the central nervous system, leading to a range of cognitive, motor, and sensory impairments. In recent years, there has been growing interest in the association between neurodegenerative diseases and olfactory dysfunction (OD). Characterized by a decline in the ability to detect or identify odors, OD has been observed in various conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). This phenomenon often precedes the onset of other clinical symptoms, suggesting its potential utility as an early marker or prodromal symptom of neurodegenerative diseases. This review provides a vast literature overview on the current knowledge of OD in PD, AD, ALS, and HD in order to evaluate its potential as a biomarker, particularly in the early and prodromal stages of these diseases. We summarize the most common methods used to measure olfactory function and delve into neuropathological correlations and the alterations in neurotransmitter systems associated with OD in those neurodegenerative diseases, including differences in genetic variants if applicable, and cater to current pitfalls and shortcomings in the research.

55Pattern of Smell Identification Impairment in Alzheimer's Disease.PubMed

Latha Velayudhan, Amy Gasper, Megan Pritchard, et al.
J Alzheimers Dis. 2015;46(2):381-7. doi: 10.3233/JAD-142838.
Olfactory dysfunction in general, and impaired odor identification in particular, have been reported in Alzheimer's disease (AD). Olfactory testing may be a useful diagnostic aid for AD, but the types of odor most commonly affected need to be identified. This study aimed to determine pattern and types of odor affected in AD with the goal of improving clinical applicability. 54 outpatients with mild to moderate AD and 40 age and gender-matched non-demented controls (NDC) were tested using British version of University of Pennsylvania Smell Identification Test (UPSIT; Sensonics, Inc., Haddon Heights, NJ) and data analyzed to identify an optimal subset of UPSIT to best differentiate AD patients from controls. AD subjects had significantly lower UPSIT total scores than NDC. Random Forest with backward elimination identified 12 UPSIT items which accurately differentiated AD patients compared to controls (sensitivity, 0.89 and specificity, 0.83, positive predictive value of 0.889, and negative predictive value of 0.833). The 12 smell items found to be most affected in AD subjects reflects important attributes such as safety and food, known to be affected in people with AD and that has the potential to impair activities of daily living. The 12 items of British UPSIT most affected in AD subjects provides a potential brief scale for early detection of AD in clinical settings. Independent replication is needed to validate these findings.

56Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer's Disease.PubMed

Liliana Ramirez-Gomez, Mark W Albers, Ana Baena, et al.
J Alzheimers Dis. 2022;88(2):721-729. doi: 10.3233/JAD-220075.
BACKGROUND: Olfactory dysfunction is one of the earliest signs of Alzheimer's disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. OBJECTIVE: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. METHODS: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. RESULTS: Worse olfactory identification performance was associated with greater age in mutation carriers (r = -0.52 p = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r = 0.55, p = 0.024) and CERAD delayed recall (r = 0.63, p = 0.007) and greater cortical amyloid-β (r = -0.53, p = 0.042) and tau pathology burden (entorhinal: r = -0.59, p = 0.016; inferior temporal: r = -0.52, p = 0.038). CONCLUSION: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.

57Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer's disease.PubMed

Carolin Meyer, Theresa Niedermeier, Paul L C Feyen, et al.
Nat Commun. 2025 Aug 8;16(1):7338. doi: 10.1038/s41467-025-62500-8.
Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Prodromal AD patients display elevated TSPO-PET signals in the OB, similarly to App mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer's disease.

58Linking Social Cognition, Parvalbumin Interneurons, and Oxytocin in Alzheimer's Disease: An Update.PubMed

Daniela Černotová, Karolína Hrůzová, David Levčík, et al.
J Alzheimers Dis. 2023;96(3):861-875. doi: 10.3233/JAD-230333.
Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.

59Early social deficits in TgF344-AD rats are accompanied by sex-specific parvalbumin-positive interneuron reduction and altered brain oscillations in the hippocampal CA2.PubMed

Daniela Černotová, Karolína Hrůzová, Jan Touš, et al.
Neurobiol Dis. 2025 May;208:106875. doi: 10.1016/j.nbd.2025.106875. Epub 2025 Mar 15.
Social withdrawal and deficits in social cognition are hallmarks of Alzheimer's disease (AD). While early deficits in social behavior and memory have been documented in mouse AD models, they remain understudied in rat models. Early-stage AD is accompanied by dysfunction of parvalbumin-positive (PV+) interneurons, implicating their potential connection to early symptoms. In this study, we employed a 5-trial social memory task to investigate early deficits in social cognition in 6-month-old TgF344-AD male and female rats. We counted the number of PV+ interneurons and recorded local field potentials during social interactions in the hippocampal CA2 - a region critical for social information processing. Our results show decreased social interest and novelty preference in TgF344-AD male and female rats. However, reduced PV+ interneuron numbers were observed only in female rats and specific to the CA2 area. The electrophysiological recordings revealed reduced theta-gamma phase-amplitude coupling in the CA2 during direct social interactions. We conclude that deficits in social cognition accompany early-stage AD in TgF344-AD rats and are potentially linked to PV+ interneuron and brain oscillatory dysfunction in the CA2 region of the hippocampus.

60Personality, Aging, and Alzheimer's Disease: Implications for Psychoneuroimmunology and Personalized Medicine.PubMed

Qing Yan
Methods Mol Biol. 2025;2868:37-48. doi: 10.1007/978-1-0716-4200-9_3.
Psychoneuroimmunology (PNI) advancements may revolutionize personalized medicine by identifying systemic biomarkers that enhance diagnosis and treatment. Inflammatory pathways connect personality traits with cognitive performance, aging-related disorders, and mortality risks. Studies have demonstrated the critical interactions between personality and various biological systems like the hypothalamic-pituitary-adrenal (HPA) axis. The gut-brain axis also affects behaviors and psychological states in older adults, with specific gut microbiota influencing cognition, mood, and personality. These findings underscore the practical implications of understanding personality-biology interactions. They can support preventive and personalized medicine for aging-associated disorders. Specifically, personality changes are prevalent in Alzheimer's disease (AD) patients, impacting clinical management and caregiver stress. Non-cognitive factors, such as personality traits and psychiatric symptoms, may serve as early markers of AD. Traits like high Neuroticism and low Openness can predict initial AD stages, often before a formal diagnosis. Personality alterations in AD are also linked to cerebrospinal fluid (CSF) and vascular imaging biomarkers, which can track AD pathology and serve as predictors. Dynamic personality assessment can aid in timely diagnosis, monitoring progression, and evaluating treatments of AD. Understanding personality traits is crucial for predicting burnout, lifespan, and intervention success. Integrating personality and PNI biomarkers into patient profiles will support the development of personalized and systems medicine.

61Alzheimer's disease.PubMed

Vanessa J De-Paula, Marcia Radanovic, Breno S Diniz, et al.
Subcell Biochem. 2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14.
Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Aβ by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.

62Pathophysiology of Alzheimer's Disease.PubMed

Brandon C Yarns, Kelsey A Holiday, David M Carlson, et al.
Psychiatr Clin North Am. 2022 Dec;45(4):663-676. doi: 10.1016/j.psc.2022.07.003. Epub 2022 Oct 14.
Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia worldwide. While neuritic plaques consisting of aggregated amyloid-beta proteins and neurofibrillary tangles of accumulated tau proteins represent the pathophysiologic hallmarks of AD, numerous processes likely interact with risk and protective factors and one's culture to produce the cognitive loss, neuropsychiatric symptoms, and functional impairments that characterize AD dementia. Recent biomarker and neuroimaging research has revealed how the pathophysiology of AD may lead to symptoms, and as the pathophysiology of AD gains clarity, more potential treatments are emerging that aim to modify the disease and relieve its burden.

63Microglial dysfunction connects depression and Alzheimer's disease.PubMed

Luís Eduardo Santos, Danielle Beckman, Sergio T Ferreira
Brain Behav Immun. 2016 Jul;55:151-165. doi: 10.1016/j.bbi.2015.11.011. Epub 2015 Nov 27.
Alzheimer's disease (AD) and major depressive disorder (MDD) are highly prevalent neuropsychiatric conditions with intriguing epidemiological overlaps. Depressed patients are at increased risk of developing late-onset AD, and around one in four AD patients are co-diagnosed with MDD. Microglia are the main cellular effectors of innate immunity in the brain, and their activation is central to neuroinflammation - a ubiquitous process in brain pathology, thought to be a causal factor of both AD and MDD. Microglia serve several physiological functions, including roles in synaptic plasticity and neurogenesis, which may be disrupted in neuroinflammation. Following early work on the 'sickness behavior' of humans and other animals, microglia-derived inflammatory cytokines have been shown to produce depressive-like symptoms when administered exogenously or released in response to infection. MDD patients consistently show increased circulating levels of pro-inflammatory cytokines, and anti-inflammatory drugs show promise for treating depression. Activated microglia are abundant in the AD brain, and concentrate around senile plaques, hallmark lesions composed of aggregated amyloid-β peptide (Aβ). The Aβ burden in affected brains is regulated largely by microglial clearance, and the complex activation state of microglia may be crucial for AD progression. Intriguingly, recent reports have linked soluble Aβ oligomers, toxins that accumulate in AD brains and are thought to cause memory impairment, to increased brain cytokine production and depressive-like behavior in mice. Here, we review recent findings supporting the inflammatory hypotheses of AD and MDD, focusing on microglia as a common player and therapeutic target linking these devastating disorders.

64Nicotinic Acetylcholine Receptors and Microglia as Therapeutic and Imaging Targets in Alzheimer's Disease.PubMed

Kazuyuki Takata, Hiroyuki Kimura, Daijiro Yanagisawa, et al.
Molecules. 2022 Apr 27;27(9):2780. doi: 10.3390/molecules27092780.
Amyloid-β (Aβ) accumulation and tauopathy are considered the pathological hallmarks of Alzheimer's disease (AD), but attenuation in choline signaling, including decreased nicotinic acetylcholine receptors (nAChRs), is evident in the early phase of AD. Currently, there are no drugs that can suppress the progression of AD due to a limited understanding of AD pathophysiology. For this, diagnostic methods that can assess disease progression non-invasively before the onset of AD symptoms are essential, and it would be valuable to incorporate the concept of neurotheranostics, which simultaneously enables diagnosis and treatment. The neuroprotective pathways activated by nAChRs are attractive targets as these receptors may regulate microglial-mediated neuroinflammation. Microglia exhibit both pro- and anti-inflammatory functions that could be modulated to mitigate AD pathogenesis. Currently, single-cell analysis is identifying microglial subpopulations that may have specific functions in different stages of AD pathologies. Thus, the ability to image nAChRs and microglia in AD according to the stage of the disease in the living brain may lead to the development of new diagnostic and therapeutic methods. In this review, we summarize and discuss the recent findings on the nAChRs and microglia, as well as their methods for live imaging in the context of diagnosis, prophylaxis, and therapy for AD.

65The Amyloid-Beta Clearance: From Molecular Targets to Glial and Neural Cells.PubMed

Wenjun Cai, Tong Wu, Ning Chen
Biomolecules. 2023 Feb 7;13(2):313. doi: 10.3390/biom13020313.
The deposition of amyloid-beta (Aβ) plaques in the brain is one of the primary pathological characteristics of Alzheimer's disease (AD). It can take place 20-30 years before the onset of clinical symptoms. The imbalance between the production and the clearance of Aβ is one of the major causes of AD. Enhancing Aβ clearance at an early stage is an attractive preventive and therapeutic strategy of AD. Direct inhibition of Aβ production and aggregation using small molecules, peptides, and monoclonal antibody drugs has not yielded satisfactory efficacy in clinical trials for decades. Novel approaches are required to understand and combat Aβ deposition. Neurological dysfunction is a complex process that integrates the functions of different types of cells in the brain. The role of non-neurons in AD has not been fully elucidated. An in-depth understanding of the interactions between neurons and non-neurons can contribute to the elucidation of Aβ formation and the identification of effective drug targets. AD patient-derived pluripotent stem cells (PSCs) contain complete disease background information and have the potential to differentiate into various types of neurons and non-neurons in vitro, which may bring new insight into the treatment of AD. Here, we systematically review the latest studies on Aβ clearance and clarify the roles of cell interactions among microglia, astroglia and neurons in response to Aβ plaques, which will be beneficial to explore methods for reconstructing AD disease models using inducible PSCs (iPSCs) through cell differentiation techniques and validating the applications of models in understanding the formation of Aβ plaques. This review may provide the most promising directions of finding the clues for preventing and delaying the development of AD.

66Biochemical Markers in Alzheimer's Disease.PubMed

Alessandro Rabbito, Maciej Dulewicz, Agnieszka Kulczyńska-Przybik, et al.
Int J Mol Sci. 2020 Mar 14;21(6):1989. doi: 10.3390/ijms21061989.
Alzheimer's disease (AD) is one of the most frequent neurodegenerative diseases affecting more than 35 million people in the world, and its incidence is estimated to triple by 2050. Alzheimer's disease is an age-related disease characterized by the progressive loss of memory and cognitive function, caused by the unstoppable neurodegeneration and brain atrophy. Current AD treatments only relieve the symptoms. The first molecular signs of the disease identified decades ago and were related to the tau neurofibrillary tangles and the β amyloid plaques. Despite the considerable progress in the diagnostic field, there is no certain knowledge of the specific biomarkers reflecting molecular mechanisms that trigger the symptoms of the disease. Therefore, there is an enormous need to find biomarkers useful for early diagnosis, before the first symptoms appear, and develop new therapeutic targets, which would guarantee improving patients' quality of life. Researchers from all around the world are looking for biomarkers that can be identified in different biological fluids such as plasma, serum, and cerebrospinal fluid, specific for Alzheimer's disease. In this review, we would like to resume some of the most interesting discovery in pathological mechanisms underlying Alzheimer's disease and promising biomarkers.

67Amyloid-Lowering Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.PubMed

Solana Leisher, Adriana Bohorquez, Marcus Gay, et al.
CNS Drugs. 2023 Aug;37(8):671-677. doi: 10.1007/s40263-023-01021-8. Epub 2023 Jul 20.
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Numerous biomarker studies have clearly demonstrated that AD has a long asymptomatic phase, with the development of pathology occurring at least 2 decades prior to the development of any symptoms. These pathological changes include a stepwise development of amyloid-β (Aβ) plaques, followed by tau neurofibrillary tangles and subsequently extensive neurodegeneration in the brain. In this review, we discuss the first class of drugs intended to be disease modifying to be approved by the US Food and Drug Administration (FDA) for AD-anti-Aβ monoclonal antibodies-and the scientific rationale with which they were developed.

68A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer's disease patients from controls.PubMed

Ida Pesämaa, Stephan A Müller, Sophie Robinson, et al.
Mol Neurodegener. 2023 Sep 29;18(1):70. doi: 10.1186/s13024-023-00657-w.
BACKGROUND: With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states. METHODS: Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers. Non-targeted mass spectrometry was used to identify proteomic changes in microglia and cerebrospinal fluid (CSF) of Grn- and Trem2-knockout mice. Additionally, we analyzed the proteome of GRN- and TREM2-knockout hiMGL and their conditioned media. Candidate marker proteins were tested in two independent patient cohorts, the ALLFTD cohort (GRN mutation carriers versus non-carriers), as well as the proteomic data set available from the EMIF-AD MBD study. RESULTS: We identified proteomic changes between the opposite activation states in mouse microglia and CSF, as well as in hiMGL cell lysates and conditioned media. For further verification, we analyzed the CSF proteome of heterozygous GRN mutation carriers suffering from frontotemporal dementia (FTD). We identified a panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) as potential indicators for microglial activation. Moreover, we confirmed three of these proteins (FABP3, GDI1, MDH1) to be significantly elevated in the CSF of Alzheimer's (AD) patients. Remarkably, each of these markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) from amyloid-negative individuals. CONCLUSIONS: The identified candidate proteins reflect microglia activity and may be relevant for monitoring the microglial response in clinical practice and clinical trials modulating microglial activity and amyloid deposition. Moreover, the finding that three of these markers differentiate amyloid-positive from amyloid-negative MCI cases in the AD cohort suggests that these proteins associate with a very early immune response to seeded amyloid. This is consistent with our previous findings in the Dominantly Inherited Alzheimer's Disease Network (DIAN) cohort, where soluble TREM2 increases as early as 21 years before symptom onset. Moreover, in mouse models for amyloidogenesis, seeding of amyloid is limited by physiologically active microglia further supporting their early protective role. The biological functions of some of our main candidates (FABP3, CD44, GPNMB) also further emphasize that lipid dysmetabolism may be a common feature of neurodegenerative disorders.

69The Relationship of Anxiety with Alzheimer's Disease: A Narrative Review.PubMed

Palak Patel, Arjun V Masurkar
Curr Alzheimer Res. 2021;18(5):359-371. doi: 10.2174/1567205018666210823095603.
BACKGROUND: There is an increased effort to better understand neuropsychiatric symptoms of Alzheimer's Disease (AD) as an important feature of symptomatic burden as well as potential modifiable factors of the disease process. Anxiety is one of the most common neuropsychiatric symptoms in Alzheimer's Disease (AD). A growing body of work has emerged that addresses the epidemiology and biological correlations of anxiety in AD. METHODS: Here, we review human studies in research and clinical cohorts that examined anxiety in AD. We focused on work related to prevalence across AD stages, correlation with established biomarkers, relationship with AD neuropathology and genetic risk factors, and impact on progression. RESULTS: Anxiety is prominent in the early stages and increases across the spectrum of functional stages. Biomarker relationships are strongest at the level of FDG-PET and amyloid measured via PET or cerebrospinal fluid analysis. Neuropathologically, anxiety emerges with early Braak stage tau pathology. The presence of the apolipoprotein E e4 allele is associated with increased anxiety at all stages, most notably at mild cognitive impairment. Anxiety portended a faster progression at all predementia stages. CONCLUSION: This body of work suggests a close biological relationship between anxiety and AD that begins in early stages and influences functional decline. As such, we discuss future work that would improve our understanding of this relationship and test the validity of anxiolytic treatment as disease modifying therapy for AD.

70Exploring cerebral amyloid angiopathy: Insights into pathogenesis, diagnosis, and treatment.PubMed

Mariagiovanna Cozza, Lucia Amadori, Virginia Boccardi
J Neurol Sci. 2023 Nov 15;454:120866. doi: 10.1016/j.jns.2023.120866. Epub 2023 Nov 2.
Cerebral Amyloid Angiopathy (CAA) is a neurological disorder characterized by the deposition of amyloid plaques in the walls of cerebral blood vessels. This condition poses significant challenges in terms of understanding its underlying mechanisms, accurate diagnosis, and effective treatment strategies. This article aims to shed light on the complexities of CAA by providing insights into its pathogenesis, diagnosis, and treatment options. The pathogenesis of CAA involves the accumulation of amyloid beta (Aβ) peptides in cerebral vessels, leading to vessel damage, impaired blood flow, and subsequent cognitive decline. Various genetic and environmental factors contribute to the development and progression of CAA, and understanding these factors is crucial for targeted interventions. Accurate diagnosis of CAA often requires advanced imaging techniques, such as magnetic resonance imaging (MRI) or positron emission tomography (PET) scans, to detect characteristic amyloid deposits in the brain. Early and accurate diagnosis enables appropriate management and intervention strategies. Treatment of CAA focuses on preventing further deposition of amyloid plaques, managing associated symptoms, and reducing the risk of complications such as cerebral hemorrhage. Currently, there are no disease-modifying therapies specifically approved for CAA. However, several experimental treatments targeting Aβ clearance and anti-inflammatory approaches are being investigated in clinical trials, offering hope for future therapeutic advancements.

71Tau-targeting therapies for Alzheimer disease.PubMed

Erin E Congdon, Einar M Sigurdsson
Nat Rev Neurol. 2018 Jul;14(7):399-415. doi: 10.1038/s41582-018-0013-z.
Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.

72Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials.PubMed

Rik Ossenkoppele, Rik van der Kant, Oskar Hansson
Lancet Neurol. 2022 Aug;21(8):726-734. doi: 10.1016/S1474-4422(22)00168-5. Epub 2022 May 25.
BACKGROUND: Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials. RECENT DEVELOPMENTS: Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.

73Typical and atypical appearance of early-onset Alzheimer's disease: A clinical, neuroimaging and neuropathological study.PubMed

Shinobu Kawakatsu, Ryota Kobayashi, Hiroshi Hayashi
Neuropathology. 2017 Apr;37(2):150-173. doi: 10.1111/neup.12364. Epub 2017 Jan 17.
The International Working Group (IWG) has classified Alzheimer's disease (AD) as two different types, the typical form and the atypical form, but clinicopathological studies of atypical AD are limited. Because atypical AD cases usually present with early-onset dementia, we investigated 12 patients with early-onset AD, including two patients with typical AD and 10 patients with atypical AD. Of these patients, six had the posterior variant, three had the frontal variant and one had the logopenic variant mixed with semantic dementia. We reported MRI, single-photon emission CT and neuropathological findings in six representative cases. We also described a "left temporal variant" of AD presenting with transcortical cortical sensory aphasia, which has not been reported previously and is another subtype of the posterior variant of AD. We found a significant correlation between regional cerebral blood flow and counts of NFTs in the cerebral cortices. An atypical presentation with focal neuropsychological symptoms roughly correlated with the density of NFTs in the cerebral cortex and more directly related to spongiform changes in the superficial layers of these areas. In contrast, the distribution of amyloid depositions was diffuse and did not necessarily correlate with focal neuropsychological symptoms. Braak staging or ABC score is not necessarily appropriate to evaluate atypical AD, and instead, spongiform changes in addition to tau pathology in the association cortices better explain the diversity of atypical AD. Interestingly, another patient with a posterior variant of AD had a novel type of atypical plaque, which we referred to as "lucent plaque". They were recognizable with HE staining in the circumference and dystrophic neurites were abundant with Gallyas-Braak staining. These plaques demonstrated intense immunoreactivity to both tau AT-8 and amyloid β (Aβ), suggesting a peculiar coexistence pattern of amyloid and tau in these plaques. Clinicopathological studies of atypical AD will provide a new understanding of the pathophysiology of AD.

74Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.PubMed

John R Sims, Jennifer A Zimmer, Cynthia D Evans, et al.
JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239.
IMPORTANCE: There are limited efficacious treatments for Alzheimer disease. OBJECTIVE: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. DESIGN, SETTING, AND PARTICIPANTS: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). INTERVENTIONS: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. MAIN OUTCOMES AND MEASURES: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. RESULTS: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. CONCLUSIONS AND RELEVANCE: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.

75Minimal clinically important difference in Alzheimer's disease: Rapid review.PubMed

Ryan T Muir, Michael D Hill, Sandra E Black, et al.
Alzheimers Dement. 2024 May;20(5):3352-3363. doi: 10.1002/alz.13770. Epub 2024 Apr 1.
INTRODUCTION: We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints. METHODS: Two reviewers searched EMBASE, MEDLINE, and PubMed from inception to June 4, 2023. RESULTS: Ten articles were retrieved. For mild cognitive impairment (MCI), a change of +2 to +3 points on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), +1 points on the Clinical Dementia Rating scale sum of boxes (CDR-SB), -5 points on the integrated Alzheimer's Disease Rating Scale (iADRS), or -1 to -2 points on the Mini-Mental State Examination (MMSE) was considered meaningful. For patients with mild AD, a change of +3 on the ADAS-Cog, +2 points on CDR-SB, -9 points on the iADRS, or -2 points on the MMSE was considered meaningful. For patients with moderate to severe AD, a change of +2 points on the CDR-SB or a change of -1.4 to -3 points on the MMSE was considered meaningful. CONCLUSION: This review identified previously published MCIDs for AD trial endpoints. Input from patients and caregivers will be needed to derive more meaningful endpoints and thresholds. HIGHLIGHTS: This systematic rapid review identified thresholds for minimal clinically important differences (MCIDs) for recently used Alzheimer's disease (AD) trial endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating scale sum of boxes (CDR-SB), integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE). MCIDs were higher for more severe stages of AD. Average treatment effects in recent trials of anti-amyloid disease modifying monoclonal antibodies are lower than previously published MCIDs. In future trials of disease modifying treatments for AD, the proportion of participants in each treatment group that experienced a clinically meaningful decline could be reported. More work is needed to incorporate the values and preferences of patients and care partners in deriving MCIDs.

76Assessing clinical progression measures in Alzheimer's disease trials: A systematic review and meta-analysis.PubMed

Jonathan McLaughlin, William J Scotton, Natalie S Ryan, et al.
Alzheimers Dement. 2024 Dec;20(12):8673-8683. doi: 10.1002/alz.14314. Epub 2024 Oct 22.
INTRODUCTION: Assessing treatments for Alzheimer's disease (AD) relies on reliable tools for measuring AD progression. In this analysis, we evaluate the sensitivity of clinical progression measures in AD within randomized controlled trials (RCTs) with confirmed positive amyloid (Aβ+) status prior to trial enrollment. METHODS: Excluding trials targeting non-cognitive symptoms, we conducted meta-analyses on progression measures from 25 selected RCTs using R version 4.2.0, along with the metafor and emmeans libraries. RESULTS: The Functional Activities Questionnaire (FAQ) demonstrated the greatest sensitivity over 12 weeks. Other cognitive measures demonstrated lower sensitivity. The integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) seemed more effective than their individual cognitive components. Neuropsychiatric measures were the least sensitive in measuring progression. DISCUSSION: Functional measures generally outperformed other measure categories. Purely cognitive domain-based measures were suboptimal for tracking early AD progression. Ideally, future measures should incorporate both cognitive and functional components to enhance sensitivity. HIGHLIGHTS: Concerns remain regarding the limitations of current outcome measures used in AD clinical trials, particularly their sensitivity in the early and preclinical stages of the disease, which hampers their reliability as indicators of AD progression. The Functional Activities Questionnaire (FAQ) demonstrated the most substantial weighted mean change over 12 weeks, followed by the Mini-Mental State Examination (MMSE). Functional measures outperformed other measure categories. Composite scores of integrated Alzheimer's Disease Rating Scale and Clinical Dementia Rating-Sum of Boxes are more sensitive to change than their individual cognitive components, possibly driven by the functional components of the score. Neuropsychiatric measures analyzed in this study appeared to be the least sensitive in measuring progression.

77A new rating scale for Alzheimer's disease.PubMed

W G Rosen, R C Mohs, K L Davis
Am J Psychiatry. 1984 Nov;141(11):1356-64. doi: 10.1176/ajp.141.11.1356.
A new rating instrument, the Alzheimer's Disease Assessment Scale, was designed specifically to evaluate the severity of cognitive and noncognitive behavioral dysfunctions characteristic of persons with Alzheimer's disease. Item descriptions, administration procedures, and scoring are outlined. Twenty-seven subjects with Alzheimer's disease and 28 normal elderly subjects were rated on 40 items. Twenty-one items with significant intraclass correlation coefficients for interrater reliability (range, .650-.989) and significant Spearman rank-order correlation coefficients for test-retest reliability (range, .514-1) constitute the final scale. Subjects with Alzheimer's disease had significantly more cognitive and noncognitive dysfunction than the normal elderly subjects.

78Brief Cognitive Tests in the Case of Dementia and Alzheimer's Disease Early Diagnosis.PubMed

Maria Sagiadinou, Antonia Plerou
Adv Exp Med Biol. 2020;1195:127-135. doi: 10.1007/978-3-030-32633-3_17.
Nowadays, Alzheimer's disease (AD) diagnosis is considered to be a crucial and extremely complex process. Nevertheless, psychometric tools, like Mini-Mental State Evaluation (MMSE), are used to address cognitive function assessment and clinical evaluation processes. However, MMSE's sensitivity in the diagnosis of mild cognitive impairment is debatable in terms of education, age, or nationality. Typical psychometric tools with the use of "paper and pencil" methods combined with physiology measurements are proposed in order to enhance validity and effectiveness in the case of Alzheimer's disease cognitive deficits. The objective of this review study is to highlight the effectiveness of brief cognitive tests (BCT) in the case of dementia and Alzheimer's disease screening. Authors' future work will focus on the application of BCT in MCI diagnosis and evaluation.

79Longitudinal verbal fluency in normal aging, preclinical, and prevalent Alzheimer's disease.PubMed

Linda J Clark, Margaret Gatz, Ling Zheng, et al.
Am J Alzheimers Dis Other Demen. 2009;24(6):461-8. doi: 10.1177/1533317509345154. Epub 2009 Sep 16.
BACKGROUND: Few longitudinal studies evaluate differences in patterns of change of category compared to letter fluency across the spectrum of cognitive impairment. METHODS: We compared change in category (animal and supermarket) and letter (F, A, S) fluency among 239 participants in 3 groups: remained cognitively normal throughout follow-up (n = 96), developed Alzheimer's Disease (AD; preclinical AD, n = 21), and with AD at initial testing (prevalent AD, n = 122). RESULTS: At baseline, prevalent and preclinical AD groups scored lower on animal than letter fluency. On all fluency measures, the prevalent AD declined faster than other groups (all P < .0001), and preclinical AD declined faster than unimpaired (all P <or= .02). Overall, animal fluency declined faster than letter fluency; animal fluency declined significantly faster than letter fluency among cognitively normal and prevalent AD participants. CONCLUSION: Greater longitudinal declines in category compared to letter fluency are consistent with cross-sectional studies. Steeper declines on both fluency measures distinguish preclinical AD from cognitively unimpaired individuals.

80Neuropsychological Performance in Alzheimer's Disease versus Late-Life Depression: A Systematic Review and Meta-Analysis.PubMed

Brianna D Barlet, Alexander O Hauson, Anna A Pollard, et al.
Arch Clin Neuropsychol. 2023 Oct 20;38(7):991-1016. doi: 10.1093/arclin/acad036.
OBJECTIVE: Despite decades of research, neuropsychological tests (NPTs) that clearly differentiate between Alzheimer's disease (AD) and late-life depression (LLD) have yet to be agreed upon. Given this gap in knowledge and the rapid deployment of disease-modifying drugs for the two disorders, accurate clinical diagnosis using evidence-based assessment is essential. This study aims to systematically examine the literature to identify NPTs that would be able to differentiate AD and LLD. METHOD: Databases and bibliographies were searched to identify articles for analysis. Two major inclusion criteria were that the studies compared neuropsychological functioning of AD versus LLD using normed NPTs and provided data for effect size calculation. Risk of bias was minimized by having independent coders for all steps in the review. RESULTS: Forty-one studies met inclusion criteria (N = 2,797) and provided effect sizes for tests that were classified as belonging to 15 domains of functioning. The two groups were well differentiated by tasks of delayed contextual verbal memory as compared to immediate or non-contextual memory, recognition cueing, confrontation naming, visuospatial construction, and conceptualization. Specific NPTs that appear to be useful for differential diagnosis include the Rey Auditory Verbal Learning Test-Delayed Recognition; Boston Naming Test; the Dementia Rating Scale's memory, conceptualization, and construction subscales; and the CERAD Constructional Praxis. CONCLUSIONS: The NPTs highlighted in this systematic review could be used as a relatively simple and cost-effective method to differentiate between patients with cognitive dysfunction due to AD versus LLD.

81NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.PubMed

Clifford R Jack, David A Bennett, Kaj Blennow, et al.
Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018.
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

82CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.PubMed

Bob Olsson, Ronald Lautner, Ulf Andreasson, et al.
Lancet Neurol. 2016 Jun;15(7):673-684. doi: 10.1016/S1474-4422(16)00070-3. Epub 2016 Apr 8.
BACKGROUND: Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aβ42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease. METHODS: In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aβ42, Aβ40, Aβ38, sAPPα, and sAPPβ), tangle pathology (P-tau), blood-brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline. FINDINGS: Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44-2·64, p<0·0001), P-tau (1·88, 1·79-1·97, p<0·0001), and Aβ42 (0·56, 0·55-0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aβ42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90-2·91, p<0·0001) and plasma T-tau (1·95, 1·12-3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28-1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples. INTERPRETATION: The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aβ42 and Aβ40 were not. Due to their consistency, T-tau, P-tau, Aβ42, and NFL in CSF should be used in clinical practice and clinical research. FUNDING: Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.

83Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis.PubMed

Maria Bjerke, Sebastiaan Engelborghs
J Alzheimers Dis. 2018;62(3):1199-1209. doi: 10.3233/JAD-170680.
An accurate and early diagnosis of Alzheimer's disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.

84Blood biomarkers in Alzheimer's disease.PubMed

M Altuna-Azkargorta, M Mendioroz-Iriarte
Neurologia (Engl Ed). 2021 Nov-Dec;36(9):704-710. doi: 10.1016/j.nrleng.2018.03.006. Epub 2020 Feb 19.
INTRODUCTION: Early diagnosis of Alzheimer disease (AD) through the use of biomarkers could assist in the implementation and monitoring of early therapeutic interventions, and has the potential to significantly modify the course of the disease. DEVELOPMENT: The classic cerebrospinal fluid and approved structural and functional neuroimaging biomarkers are of limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would increase their use in clinical practice. We review the available published evidence on the main blood biochemical biomarkers potentially useful for diagnosing AD. CONCLUSIONS: Blood biomarkers are more cost- and time-effective than CSF biomarkers. However, immediate applicability in clinical practice is relatively unlikely. The main limitations come from the difficulty of measuring and standardising thresholds between different laboratories and the failure to replicate results. Of all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through "omics" approaches, such as isolated or combined metabolomics, offer the most promising results.

85Biomarkers in Alzheimer's disease.PubMed

Kayalvizhi Rajendran, Uma Maheswari Krishnan
Clin Chim Acta. 2024 Aug 15;562:119857. doi: 10.1016/j.cca.2024.119857. Epub 2024 Jul 8.
Alzheimer's disease (AD) is among the most common neurodegenerative disorders. AD is characterized by deposition of neurofibrillary tangles and amyloid plaques, leading to associated secondary pathologies, progressive neurodegeneration, and eventually death. Currently used diagnostics are largely image-based, lack accuracy and do not detect early disease, ie, prior to onset of symptoms, thus limiting treatment options and outcomes. Although biomarkers such as amyloid-β and tau protein in cerebrospinal fluid have gained much attention, these are generally limited to disease progression. Unfortunately, identification of biomarkers for early and accurate diagnosis remains a challenge. As such, body fluids such as sweat, serum, saliva, mucosa, tears, and urine are under investigation as alternative sources for biomarkers that can aid in early disease detection. This review focuses on biomarkers identified through proteomics in various biofluids and their potential for early and accurate diagnosis of AD.

86Advances in the development of new biomarkers for Alzheimer's disease.PubMed

Timofey O Klyucherev, Pawel Olszewski, Alena A Shalimova, et al.
Transl Neurodegener. 2022 Apr 21;11(1):25. doi: 10.1186/s40035-022-00296-z.
Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.

87Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.PubMed

Elisabeth H Thijssen, Renaud La Joie, Amelia Strom, et al.
Lancet Neurol. 2021 Sep;20(9):739-752. doi: 10.1016/S1474-4422(21)00214-3.
BACKGROUND: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. METHODS: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. FINDINGS: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; p=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; p=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; p=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; p=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; p<0·0001, n=230). INTERPRETATION: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. FUNDING: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

88Plasma phospho-tau in Alzheimer's disease: towards diagnostic and therapeutic trial applications.PubMed

Fernando Gonzalez-Ortiz, Przemysław R Kac, Wagner S Brum, et al.
Mol Neurodegener. 2023 Mar 16;18(1):18. doi: 10.1186/s13024-023-00605-8.
As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis. Blood biomarkers have the capacity to help expand access to AD diagnostics worldwide. One such promising biomarker is plasma phosphorylated tau (p-tau), which has demonstrated specificity to AD versus non-AD neurodegenerative diseases, and will be extremely important to inform on clinical diagnosis and eligibility for therapies that have recently been approved. This review provides an update on the diagnostic and prognostic performances of plasma p-tau181, p-tau217 and p-tau231, and their associations with in vivo and autopsy-verified diagnosis and pathological hallmarks. Additionally, we discuss potential applications and unanswered questions of plasma p-tau for therapeutic trials, given their recent addition to the biomarker toolbox for participant screening, recruitment and during-trial monitoring. Outstanding questions include assay standardization, threshold generation and biomarker verification in diverse cohorts reflective of the wider community attending memory clinics and included in clinical trials.

89Performance of plasma phosphorylated tau 181 and 217 in the community.PubMed

Michelle M Mielke, Jeffrey L Dage, Ryan D Frank, et al.
Nat Med. 2022 Jul;28(7):1398-1405. doi: 10.1038/s41591-022-01822-2. Epub 2022 May 26.
Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30-98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81-0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.

90Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.PubMed

Robert A Rissman, Oliver Langford, Rema Raman, et al.
Alzheimers Dement. 2024 Feb;20(2):1214-1224. doi: 10.1002/alz.13542. Epub 2023 Nov 6.
INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. METHODS: Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

91Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care.PubMed

Sebastian Palmqvist, Pontus Tideman, Niklas Mattsson-Carlgren, et al.
JAMA. 2024 Oct 15;332(15):1245-1257. doi: 10.1001/jama.2024.13855.
IMPORTANCE: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. OBJECTIVE: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values. DESIGN, SETTING, AND PARTICIPANTS: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection. EXPOSURE: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2]). MAIN OUTCOMES AND MEASURES: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated. RESULTS: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]). CONCLUSIONS AND RELEVANCE: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.

92Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.PubMed

Fernando Gonzalez-Ortiz, Michael Turton, Przemysław R Kac, et al.
Brain. 2023 Mar 1;146(3):1152-1165. doi: 10.1093/brain/awac407.
Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.

93Compositional and functional gut microbiota alterations in mild cognitive impairment: links to Alzheimer's disease pathology.PubMed

Kang-Chen Fan, Chen-Ching Lin, Yen-Ling Chiu, et al.
Alzheimers Res Ther. 2025 May 30;17(1):122. doi: 10.1186/s13195-025-01769-9.
BACKGROUND: Emerging evidence highlights the bidirectional communication between the gut microbiota and the brain, suggesting a potential role for gut dysbiosis in Alzheimer's disease (AD) pathology and cognitive decline. Existing literature on gut microbiota lacks species-level insights. This study investigates gut microbiota alterations in mild cognitive impairment (MCI), focusing on their association with comprehensive AD biomarkers, including amyloid burden, tau pathology, neurodegeneration, and cognitive performance. METHODS: We analyzed fecal samples from 119 individuals with MCI and 320 cognitively normal controls enrolled in the Taiwan Precision Medicine Initiative on Cognitive Impairment and Dementia cohort. Shotgun metagenomic sequencing was conducted with taxonomic profiling using MetaPhlAn4. Amyloid burden and plasma pTau181 were quantified via PET imaging and Simoa assays, respectively, while APOE genotyping was performed using TaqMan assays. Microbial diversity, differential abundance analysis, and correlation mapping with neuropsychological and neuroimaging measures were conducted to identify gut microbiota species signatures associated with MCI and AD biomarkers. RESULTS: We identified 59 key microbial species linked to MCI and AD biomarkers. Notably, species within the same genera, such as Bacteroides and Ruminococcus, showed opposing effects, while Akkermansia muciniphila correlated with reduced amyloid burden, suggesting a protective role. Functional profiling revealed microbial pathways contributing to energy metabolism and neuroinflammation, mediating the relationship between gut microbes and brain health. Co-occurrence network analyses demonstrated complex microbial interactions, indicating that the collective influence of gut microbiota on neurodegeneration. CONCLUSIONS: Our findings challenge genus-level microbiome analyses, revealing species-specific modulators of AD pathology. This study highlights gut microbial activity as a potential therapeutic target to mitigate cognitive decline and neurodegeneration.

94Updated appropriate use criteria for amyloid and tau PET: A report from the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging Workgroup.PubMed

Gil D Rabinovici, David S Knopman, Javier Arbizu, et al.
Alzheimers Dement. 2025 Jan;21(1):e14338. doi: 10.1002/alz.14338. Epub 2025 Jan 8.
INTRODUCTION: The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities. RESULTS: For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. HIGHLIGHTS: A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

95Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.PubMed

Suzanne E Schindler, Douglas Galasko, Ana C Pereira, et al.
Nat Rev Neurol. 2024 Jul;20(7):426-439. doi: 10.1038/s41582-024-00977-5. Epub 2024 Jun 12.
Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

96Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?PubMed

Martin Vyhnalek, Martina Laczó, Jan Laczó
J Alzheimers Dis. 2024;101(4):1133-1136. doi: 10.3233/JAD-240660.
Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

97Functional magnetic resonance imaging, deep learning, and Alzheimer's disease: A systematic review.PubMed

Samuel L Warren, Ahmed A Moustafa
J Neuroimaging. 2023 Jan;33(1):5-18. doi: 10.1111/jon.13063. Epub 2022 Oct 18.
Alzheimer's disease (AD) is currently diagnosed using a mixture of psychological tests and clinical observations. However, these diagnoses are not perfect, and additional diagnostic tools (e.g., MRI) can help improve our understanding of AD as well as our ability to detect the disease. Accordingly, a large amount of research has been invested into innovative diagnostic methods for AD. Functional MRI (fMRI) is a form of neuroimaging technology that has been used to diagnose AD; however, fMRI is incredibly noisy, complex, and thus lacks clinical use. Nonetheless, recent innovations in deep learning technology could enable the simplified and streamlined analysis of fMRI. Deep learning is a form of artificial intelligence that uses computer algorithms based on human neural networks to solve complex problems. For example, in fMRI research, deep learning models can automatically denoise images and classify AD by detecting patterns in participants' brain scans. In this systematic review, we investigate how fMRI (specifically resting-state fMRI) and deep learning methods are used to diagnose AD. In turn, we outline the common deep neural network, preprocessing, and classification methods used in the literature. We also discuss the accuracy, strengths, limitations, and future direction of fMRI deep learning methods. In turn, we aim to summarize the current field for new researchers, suggest specific areas for future research, and highlight the potential of fMRI to aid AD diagnoses.

98AI-driven innovations in Alzheimer's disease: Integrating early diagnosis, personalized treatment, and prognostic modelling.PubMed

Mayur Kale, Nitu Wankhede, Rupali Pawar, et al.
Ageing Res Rev. 2024 Nov;101:102497. doi: 10.1016/j.arr.2024.102497. Epub 2024 Sep 16.
Alzheimer's disease (AD) presents a significant challenge in neurodegenerative research and clinical practice due to its complex etiology and progressive nature. The integration of artificial intelligence (AI) into the diagnosis, treatment, and prognostic modelling of AD holds promising potential to transform the landscape of dementia care. This review explores recent advancements in AI applications across various stages of AD management. In early diagnosis, AI-enhanced neuroimaging techniques, including MRI, PET, and CT scans, enable precise detection of AD biomarkers. Machine learning models analyze these images to identify patterns indicative of early cognitive decline. Additionally, AI algorithms are employed to detect genetic and proteomic biomarkers, facilitating early intervention. Cognitive and behavioral assessments have also benefited from AI, with tools that enhance the accuracy of neuropsychological tests and analyze speech and language patterns for early signs of dementia. Personalized treatment strategies have been revolutionized by AI-driven approaches. In drug discovery, virtual screening and drug repurposing, guided by predictive modelling, accelerate the identification of effective treatments. AI also aids in tailoring therapeutic interventions by predicting individual responses to treatments and monitoring patient progress, allowing for dynamic adjustment of care plans. Prognostic modelling, another critical area, utilizes AI to predict disease progression through longitudinal data analysis and risk prediction models. The integration of multi-modal data, combining clinical, genetic, and imaging information, enhances the accuracy of these predictions. Deep learning techniques are particularly effective in fusing diverse data types to uncover new insights into disease mechanisms and progression. Despite these advancements, challenges remain, including ethical considerations, data privacy, and the need for seamless integration of AI tools into clinical workflows. This review underscores the transformative potential of AI in AD management while highlighting areas for future research and development. By leveraging AI, the healthcare community can improve early diagnosis, personalize treatments, and predict disease outcomes more accurately, ultimately enhancing the quality of life for individuals with AD.

99Artificial intelligence in brain MRI analysis of Alzheimer's disease over the past 12 years: A systematic review.PubMed

Tory O Frizzell, Margit Glashutter, Careesa C Liu, et al.
Ageing Res Rev. 2022 May;77:101614. doi: 10.1016/j.arr.2022.101614. Epub 2022 Mar 28.
INTRODUCTION: Multiple structural brain changes in Alzheimer's disease (AD) and mild cognitive impairment (MCI) have been revealed on magnetic resonance imaging (MRI). There is a fast-growing effort in applying artificial intelligence (AI) to analyze these data. Here, we review and evaluate the AI studies in brain MRI analysis with synthesis. METHODS: A systematic review of the literature, spanning the years from 2009 to 2020, was completed using the PubMed database. AI studies using MRI imaging to investigate normal aging, mild cognitive impairment, and AD-dementia were retrieved for review. Bias assessment was completed using the PROBAST criteria. RESULTS: 97 relevant studies were included in the review. The studies were typically focused on the classification of AD, MCI, and normal aging (71% of the reported studies) and the prediction of MCI conversion to AD (25%). The best performance was achieved by using the deep learning-based convolution neural network algorithms (weighted average accuracy 89%), in contrast to 76-86% using Logistic Regression, Support Vector Machines, and other AI methods. DISCUSSION: The synthesized evidence is paramount to developing sophisticated AI approaches to reliably capture and quantify multiple subtle MRI changes in the whole brain that exemplify the complexity and heterogeneity of AD and brain aging.

100Artificial intelligence-based diagnosis of Alzheimer's disease with brain MRI images.PubMed

Zhaomin Yao, Hongyu Wang, Wencheng Yan, et al.
Eur J Radiol. 2023 Aug;165:110934. doi: 10.1016/j.ejrad.2023.110934. Epub 2023 Jun 20.
Alzheimer's disease, a primary neurodegenerative condition, predominantly impacts the elderly and pre-elderly population. This progressive neurological disorder is characterized by an array of symptoms including memory loss, cognitive decline, and various physiological and psychological disturbances, significantly compromising the quality of life of patients and their caregivers. Recent advancements in Magnetic Resonance Imaging (MRI) technology have catalyzed research in AI-enhanced diagnostics for Alzheimer's disease, fostering optimism for early detection and timely interventions. This progress has paved the way for the development of sophisticated algorithms and models adept at analyzing complex brain imaging data, thereby augmenting diagnostic accuracy and efficiency. This advancement fuels optimism regarding the transformative potential of AI-driven diagnostics in revolutionizing Alzheimer's disease management, with the prospect of facilitating more effective treatment strategies and improved patient outcomes. The objective of this review is to provide a comprehensive overview of recent developments in deep learning methodologies applied to brain MRI images for the classification of various stages of Alzheimer's disease, with a particular emphasis on early diagnosis. Furthermore, this review underscores the limitations of current research, discussing potential challenges and future research directions in this dynamic field.

101Development and validation of an interpretable deep learning framework for Alzheimer's disease classification.PubMed

Shangran Qiu, Prajakta S Joshi, Matthew I Miller, et al.
Brain. 2020 Jun 1;143(6):1920-1933. doi: 10.1093/brain/awaa137.
Alzheimer's disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer's disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer's disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer's disease and cognitively normal subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer's Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer's disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

102Automated classification of Alzheimer's disease and mild cognitive impairment using a single MRI and deep neural networks.PubMed

Silvia Basaia, Federica Agosta, Luca Wagner, et al.
Neuroimage Clin. 2019;21:101645. doi: 10.1016/j.nicl.2018.101645. Epub 2018 Dec 18.
We built and validated a deep learning algorithm predicting the individual diagnosis of Alzheimer's disease (AD) and mild cognitive impairment who will convert to AD (c-MCI) based on a single cross-sectional brain structural MRI scan. Convolutional neural networks (CNNs) were applied on 3D T1-weighted images from ADNI and subjects recruited at our Institute (407 healthy controls [HC], 418 AD, 280 c-MCI, 533 stable MCI [s-MCI]). CNN performance was tested in distinguishing AD, c-MCI and s-MCI. High levels of accuracy were achieved in all the classifications, with the highest rates achieved in the AD vs HC classification tests using both the ADNI dataset only (99%) and the combined ADNI + non-ADNI dataset (98%). CNNs discriminated c-MCI from s-MCI patients with an accuracy up to 75% and no difference between ADNI and non-ADNI images. CNNs provide a powerful tool for the automatic individual patient diagnosis along the AD continuum. Our method performed well without any prior feature engineering and regardless the variability of imaging protocols and scanners, demonstrating that it is exploitable by not-trained operators and likely to be generalizable to unseen patient data. CNNs may accelerate the adoption of structural MRI in routine practice to help assessment and management of patients.

103A deep learning MRI approach outperforms other biomarkers of prodromal Alzheimer's disease.PubMed

Xinyang Feng, Frank A Provenzano, Scott A Small, et al.
Alzheimers Res Ther. 2022 Mar 29;14(1):45. doi: 10.1186/s13195-022-00985-x.
BACKGROUND: The three core pathologies of Alzheimer's disease (AD) are amyloid pathology, tau pathology, and neurodegeneration. Biomarkers exist for each. Neurodegeneration is often detected by neuroimaging, and we hypothesized that a voxel-based deep learning approach using structural MRI might outperform other neuroimaging methods. METHODS: First, we implement an MRI-based deep learning model, trained with a data augmentation strategy, which classifies Alzheimer's dementia and generates class activation maps. Next, we tested the model in prodromal AD and compared its performance to other biomarkers of amyloid pathology, tau pathology, and neuroimaging biomarkers of neurodegeneration. RESULTS: The model distinguished between controls and AD with high accuracy (AUROC = 0.973) with class activation maps that localized to the hippocampal formation. As hypothesized, the model also outperformed other neuroimaging biomarkers of neurodegeneration in prodromal AD (AUROC = 0.788) but also outperformed biomarkers of amyloid (CSF Aβ = 0.702) or tau pathology (CSF tau = 0.682), and the findings are interpreted in the context of AD's known anatomical biology. CONCLUSIONS: The advantages of using deep learning to extract biomarker information from conventional MRIs extend practically, potentially reducing patient burden, risk, and cost.

104Revolutionizing early Alzheimer's disease and mild cognitive impairment diagnosis: a deep learning MRI meta-analysis.PubMed

Li-Xue Wang, Yi-Zhe Wang, Chen-Guang Han, et al.
Arq Neuropsiquiatr. 2024 Aug;82(8):1-10. doi: 10.1055/s-0044-1788657. Epub 2024 Aug 15.
BACKGROUND: The early diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains a significant challenge in neurology, with conventional methods often limited by subjectivity and variability in interpretation. Integrating deep learning with artificial intelligence (AI) in magnetic resonance imaging (MRI) analysis emerges as a transformative approach, offering the potential for unbiased, highly accurate diagnostic insights. OBJECTIVE: A meta-analysis was designed to analyze the diagnostic accuracy of deep learning of MRI images on AD and MCI models. METHODS: A meta-analysis was performed across PubMed, Embase, and Cochrane library databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on the diagnostic accuracy of deep learning. Subsequently, methodological quality was assessed using the QUADAS-2 checklist. Diagnostic measures, including sensitivity, specificity, likelihood ratios, diagnostic odds ratio, and area under the receiver operating characteristic curve (AUROC) were analyzed, alongside subgroup analyses for T1-weighted and non-T1-weighted MRI. RESULTS: A total of 18 eligible studies were identified. The Spearman correlation coefficient was -0.6506. Meta-analysis showed that the combined sensitivity and specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.84, 0.86, 6.0, 0.19, and 32, respectively. The AUROC was 0.92. The quiescent point of hierarchical summary of receiver operating characteristic (HSROC) was 3.463. Notably, the images of 12 studies were acquired by T1-weighted MRI alone, and those of the other 6 were gathered by non-T1-weighted MRI alone. CONCLUSION: Overall, deep learning of MRI for the diagnosis of AD and MCI showed good sensitivity and specificity and contributed to improving diagnostic accuracy.

105A 3D multi-modal multi-scale end-to-end classifier for Alzheimer's disease diagnosis.PubMed

M Khojaste-Sarakhsi, Seyedhamidreza Shahabi Haghighi, S M T Fatemi Ghomi
Med Eng Phys. 2025 Sep;143:104382. doi: 10.1016/j.medengphy.2025.104382. Epub 2025 Jun 23.
This study presents a novel 3D multi-modal multi-scale end-to-end classifier to enhance Alzheimer's Disease (AD) diagnosis by integrating MRI, PET, age, and MMSE cognitive test scores. Leveraging a ResNet-inspired architecture with trainable multi-scale convolutional scaling, the classifier categorizes subjects into four classes-Normal Control (NC), Stable Mild Cognitive Impairment (sMCI), Progressive Mild Cognitive Impairment (pMCI), and AD-capturing both structural and functional brain pathology. A tailored fusion strategy (MA_PC) processes MRI with age and PET with MMSE in parallel branches, optimizing complementary information use. Extensive experiments using the ADNI dataset, a five-fold cross-validation scheme, and an unseen test set demonstrate that MA_PC with convolutional scaling achieves superior performance, outperforming commonly used fusion strategies as well as pre-trained 3D ResNets designed for medical imaging applications. A comparative analysis reveals that 4-class classification consistently surpasses a 3-class approach (NC, MCI, AD), highlighting the model's ability to distinguish subtle AD progression stages. These findings highlight the critical role of advanced data fusion and scaling methods in enhancing AD diagnosis accuracy and underscore the potential of multi-modal CNNs in advancing medical imaging research.

106Multimodal deep learning for Alzheimer's disease dementia assessment.PubMed

Shangran Qiu, Matthew I Miller, Prajakta S Joshi, et al.
Nat Commun. 2022 Jun 20;13(1):3404. doi: 10.1038/s41467-022-31037-5.
Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.

107Deep Learning with Neuroimaging and Genomics in Alzheimer's Disease.PubMed

Eugene Lin, Chieh-Hsin Lin, Hsien-Yuan Lane
Int J Mol Sci. 2021 Jul 24;22(15):7911. doi: 10.3390/ijms22157911.
A growing body of evidence currently proposes that deep learning approaches can serve as an essential cornerstone for the diagnosis and prediction of Alzheimer's disease (AD). In light of the latest advancements in neuroimaging and genomics, numerous deep learning models are being exploited to distinguish AD from normal controls and/or to distinguish AD from mild cognitive impairment in recent research studies. In this review, we focus on the latest developments for AD prediction using deep learning techniques in cooperation with the principles of neuroimaging and genomics. First, we narrate various investigations that make use of deep learning algorithms to establish AD prediction using genomics or neuroimaging data. Particularly, we delineate relevant integrative neuroimaging genomics investigations that leverage deep learning methods to forecast AD on the basis of incorporating both neuroimaging and genomics data. Moreover, we outline the limitations as regards to the recent AD investigations of deep learning with neuroimaging and genomics. Finally, we depict a discussion of challenges and directions for future research. The main novelty of this work is that we summarize the major points of these investigations and scrutinize the similarities and differences among these investigations.

108The link between nutrition and Alzheimer's disease: from prevention to treatment.PubMed

Laís Bhering Martins, Ana Letícia Malheiros Silveira, Antonio Lúcio Teixeira
Neurodegener Dis Manag. 2021 Apr;11(2):155-166. doi: 10.2217/nmt-2020-0023. Epub 2021 Feb 8.
Alzheimer's disease (AD) is the most common cause of dementia. To date, there is no effective pharmacological strategy to slow or stop disease progression. In this context, multiple alternative therapeutic strategies have been investigated for AD. This review addresses the potential role of nutrition interventions in AD prevention and treatment. Nutritional strategies for AD have been based on four pillars: maintaining a healthy weight (i.e., prevention and/or treatment of obesity, especially in midlife and prevention of weight loss in the later stages of AD); correction of nutritional deficiencies; adequate consumption of micronutrients (vitamins and minerals), especially those implicated in the pathways of AD pathophysiology; and microbiota modulation.

109Mediterranean diet: The role of long-chain ω-3 fatty acids in fish; polyphenols in fruits, vegetables, cereals, coffee, tea, cacao and wine; probiotics and vitamins in prevention of stroke, age-related cognitive decline, and Alzheimer disease.PubMed

G C Román, R E Jackson, R Gadhia, et al.
Rev Neurol (Paris). 2019 Dec;175(10):724-741. doi: 10.1016/j.neurol.2019.08.005. Epub 2019 Sep 11.
The mechanisms of action of the dietary components of the Mediterranean diet are reviewed in prevention of cardiovascular disease, stroke, age-associated cognitive decline and Alzheimer disease. A companion article provides a comprehensive review of extra-virgin olive oil. The benefits of consumption of long-chain ω-3 fatty acids are described. Fresh fish provides eicosapentaenoic acid while α-linolenic acid is found in canola and soybean oils, purslane and nuts. These ω-3 fatty acids interact metabolically with ω-6 fatty acids mainly linoleic acid from corn oil, sunflower oil and peanut oil. Diets rich in ω-6 fatty acids inhibit the formation of healthier ω-3 fatty acids. The deleterious effects on lipid metabolism of excessive intake of carbohydrates, in particular high-fructose corn syrup and artificial sweeteners, are explained. The critical role of the ω-3 fatty acid docosahexaenoic acid in the developing and aging brain and in Alzheimer disease is addressed. Nutritional epidemiology studies, prospective population-based surveys, and clinical trials confirm the salutary effects of fish consumption on prevention of coronary artery disease, stroke and dementia. Recent recommendations on fish consumption by pregnant women and potential mercury toxicity are reviewed. The polyphenols and flavonoids of plant origin play a critical role in the Mediterranean diet, because of their antioxidant and anti-inflammatory properties of benefit in type-2 diabetes mellitus, cardiovascular disease, stroke and cancer prevention. Polyphenols from fruits and vegetables modulate tau hyperphosphorylation and beta amyloid aggregation in animal models of Alzheimer disease. From the public health viewpoint worldwide the daily consumption of fruits and vegetables has become the main tool for prevention of cardiovascular disease and stroke. We review the important dietary role of cereal grains in prevention of coronary disease and stroke. Polyphenols from grapes, wine and alcoholic beverages are discussed, in particular their effects on coagulation. The mechanisms of action of probiotics and vitamins are also included.

110Mediterranean diet adherence, gut microbiota, and Alzheimer's or Parkinson's disease risk: A systematic review.PubMed

Rebecca J Solch, Julia O Aigbogun, Andrew G Voyiadjis, et al.
J Neurol Sci. 2022 Mar 15;434:120166. doi: 10.1016/j.jns.2022.120166. Epub 2022 Jan 26.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative diseases, both without prevention or cure. The Mediterranean diet (MeDi) may be neuroprotective by modulating gut microbiota. We aimed to assess the effects of adherence to MeDi on the gut microbiota in relation to AD or PD risk. A search from inception to November 2020 was conducted in PubMed, CINAHL, EMBASE, Web of Science, Global Health, Biological Abstracts, and Grey Literature Report databases. Two searches were conducted: 1) (MeDi or Microbiota) and (PD or AD) and 2) MeDi and microbiota. Inclusion criteria for papers were specified prior to review. Of 4672 studies identified, 64 were eligible for inclusion. These studies were divided into five groups: MeDi and AD risk (n = 4), MeDi and PD risk (n = 2), MeDi and microbial composition or metabolomics (n = 21), AD and microbial composition or metabolomics (n = 7), and PD and microbial composition or metabolomics (n = 30). Adherence to the MeDi was associated with a lower risk of AD and PD development. Eight genera and two species of bacteria had an inverse relationship with MeDi and AD, and one family, eight genera and three species of bacteria had an inverse relationship with MeDi and PD. More studies are needed to investigate if MeDi, gut microbiota, and neurodegeneration are causally related.

111Association between Mediterranean diet and dementia and Alzheimer disease: a systematic review with meta-analysis.PubMed

Daniele Nucci, Andrea Sommariva, Luca Mario Degoni, et al.
Aging Clin Exp Res. 2024 Mar 22;36(1):77. doi: 10.1007/s40520-024-02718-6.
BACKGROUND: Dementia affects 5-8% of the population aged over 65 years (~50 million worldwide). Several factors are associated with increased risk, including diet. The Mediterranean diet (MedDiet) has shown potential protective effects against several chronic diseases. AIMS: This systematic review with meta-analysis aim was to assess the association between adherence to the MedDiet and the risk of dementia in the elderly. METHODS: PRISMA-2020 guidelines were followed. PubMed/MEDLINE and Scopus were searched on 17 July 2023. The Newcastle-Ottawa Scale tool was used to assess the risk of bias. The protocol was pre-registered in PROSPERO (registration number: CRD 42023444368). Heterogeneity was assessed using the I test. Publication bias was assessed by visual inspection of the funnel plot and by Egger's regression asymmetry test. The final effect size was reported as OR or HR, depending on the study design of the included studies. RESULTS: Out of 682 records, 21 were included in the analysis. The pooled OR was 0.89 (95% CI = 0.84-0.94) based on 65,955 participants (I = 69.94). When only cohort studies were included, HR was 0.84 (95% CI = 0.76-0.94) based on 55,205 participants (I = 89.70). When only Alzheimer Disease was considered OR was 0.73 (95% CI = 0.62-0.85) based on 38,292 participants (I = 63.85). DISCUSSION: Despite the relatively low risk reduction associated with higher adherence to MedDiet among elderly, it should be considered that this population is the most affected. CONCLUSIONS: Adherence to MedDiet could be an effective non-pharmacological measure to reduce the burden of dementia, even among elderly.

112The role of nutrition in Alzheimer's disease.PubMed

Sylwia Śliwińska, Małgorzata Jeziorek
Rocz Panstw Zakl Hig. 2021;72(1):29-39. doi: 10.32394/rpzh.2021.0154.
The aging population is a significant social, medical and economic problem due to increasing prevalence of chronic diseases in elderly population. Alzheimer's disease (AD) is the most common form of dementia and the most common neurodegenerative disease. It is characterized by a progressive deterioration of memory and cognitive function. So far, there is neither an effective prevention nor cure for dementia, so more and more attention is paid to the prevention of this group of diseases, particularly to the appropriate diet. Preventive intervention gives the best results if introduced before the first symptoms of dementia, i.e., around the age of 50. This is when the nutritional status, number of synapses, cognition, and neuropathological changes in the nervous system compensate each other, which increases the chances of staying healthy for a longer period of time. It has been proven that dietary habits, which lead to the development of cardiovascular and metabolic diseases, significantly increase the risk of dementia. On the other hand, a Mediterranean diet rich in antioxidants, fiber and omega-3 polyunsaturated fatty acids may have a protective effect on the neurodegenerative process. The beneficial effect of many nutrients on the course of AD has been demonstrated. These include: glutathione, polyphenols, curcumin, coenzyme Q10, vitamins B6, B12, folic acid, unsaturated fatty acids, lecithin, UA, caffeine and some probiotic bacteria. A diet rich in saturated fatty acids and branched-chain amino acids (BCAA) promotes the progression of dementia. Dietary intervention should be introduced as early as possible to minimize the risk of developing dementia. The Mediterranean and DASH diets have been documented to protect against AD. However, the MIND diet is reported to be much more effective in preventing cognitive decline/dementia than either the Mediterranean or DASH diets alone.

113Risk Reduction and Prevention of Alzheimer's Disease: Biological Mechanisms of Diet.PubMed

Hugo McGurran, Jordan Glenn, Erica Madero, et al.
Curr Alzheimer Res. 2020;17(5):407-427. doi: 10.2174/1567205017666200624200651.
Alzheimer's Disease (AD) incidence is increasing and with no disease modifying agents available, preventative measures through lifestyle factors are being investigated. Combined with the prevention of AD risk factors such as heart disease, diabetes, and with more recent evidence, microbiome dysfunction, there is a substantial foundation for diet as a modifiable risk factor and preventative measure for AD. Recent evidence suggests AD associated pathologies, such as oxidative stress and inflammation, can be modulated by the lipids, vitamins, and polyphenols obtained through nutritional intake. Furthermore, epidemiological and preclinical evidence has uncovered certain compounds within foods that may have beneficial effects in the prevention of AD, including omega-3 fatty acids, vitamin E, and resveratrol among others. However, clinical data examining specific compounds are often inconsistent and fail to replicate the preclinical data. On the other hand, dietary patterns such as the Mediterranean or MIND diet have shown promise in terms of clinical outcomes for patients, indicating a reductionist approach to diet is not as effective as a holistic dietary pattern. In this review, we summarize some of the biological mechanisms of key compounds in their relation to AD and how they fit into a dietary pattern that supports the role of diet as a risk reducing factor for AD.

114Diet and Inflammation in Cognitive Ageing and Alzheimer's Disease.PubMed

Andrea M McGrattan, Bernadette McGuinness, Michelle C McKinley, et al.
Curr Nutr Rep. 2019 Jun;8(2):53-65. doi: 10.1007/s13668-019-0271-4.
PURPOSE OF REVIEW: Nutrition is known to modulate the immune system and may alter neuroinflammatory processes implicated in the pathogenesis of Alzheimer's disease (AD) and progression of neurodegeneration. Here, we review the evidence for healthy dietary patterns and age-related cognition and discuss potential neuroinflammatory actions of diet on cognitive function. RECENT FINDINGS: Anti-inflammatory dietary patterns such as the Mediterranean diet (MD) and dietary approaches to stop hypertension (DASH) may be neuroprotective. Several dietary components consumed in the MD and DASH (omega-3 fatty acids, antioxidants and polyphenols) can inhibit neuroinflammation associated with AD. Anti-inflammatory diets may also attenuate neuroinflammation via indirect immune pathways from the gut microbiome and systemic circulation. Diet may influence cognitive ageing via several inflammatory pathways. However, data from human studies are lacking and the exact mechanisms linking diet to cognitive function remain elusive. Further dietary intervention studies are required to investigate diet-associated neurological change from the earliest through to latest stages of cognitive decline. Furthermore, incorporation of neuroimaging measures in intervention studies would advance current understanding of the mechanistic effects of dietary modification on neuroinflammation in the ageing brain.

115Alzheimer's disease: risk factors and potentially protective measures.PubMed

Marcos Vinícius Ferreira Silva, Cristina de Mello Gomide Loures, Luan Carlos Vieira Alves, et al.
J Biomed Sci. 2019 May 9;26(1):33. doi: 10.1186/s12929-019-0524-y.
Alzheimer's disease (AD) is the most common type of dementia and typically manifests through a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial skills deficiencies, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression. The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein (P-tau) in the neuronal cytoplasm is a remarkable pathophysiological cause in patients' brains. Approximately 70% of the risk of developing AD can be attributed to genetics. However, acquired factors such as cerebrovascular diseases, diabetes, hypertension, obesity and dyslipidemia increase the risk of AD development. The aim of the present minireview was to summarize the pathophysiological mechanism and the main risk factors for AD. As a complement, some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet will also be addressed.

116Modifying the diet and gut microbiota to prevent and manage neurodegenerative diseases.PubMed

Ellen J Gates, Anna K Bernath, Andis Klegeris
Rev Neurosci. 2022 Mar 21;33(7):767-787. doi: 10.1515/revneuro-2021-0146. Print 2022 Oct 26.
The global prevalence of Alzheimer's disease and Parkinson's disease is steadily increasing due to the aging population. The lack of effective drugs against these neurodegenerative disorders makes it imperative to identify new strategies for their prevention and treatment. Recent studies have revealed that harnessing the power of the gut microbiota through modification of diet may be a valuable approach for reducing the risk, modulating the symptoms, and ameliorating the pathophysiological aspects of neurodegenerative diseases. Consuming specific dietary components can alter the prevalence of bacterial communities within the gut to a healthy enterotype, which can influence the production of beneficial metabolites by microbiota. This article focuses on several dietary components, which have been demonstrated to affect the gut microbiota-brain axis and therefore could lead to attenuation of specific pathological processes in neurodegenerative diseases. Published evidence indicates that fermented foods, including kefir, and foods that are high in bioactive polyphenols and complex carbohydrates, such as grapes, pomegranates, and seaweed, may be effective at reducing neuroinflammation, oxidative stress, neurotransmitter dysfunction, and neuronal death associated with Alzheimer's and Parkinson's diseases. Even though experimental evidence supporting the protective properties of the above dietary components in these diseases is emerging, it is evident that further human clinical studies are required to conclusively establish the benefits of any suggested dietary interventions. The translational potential of such research is illustrated by the clinical success of the recently developed Alzheimer's drug, GV-971, which is a seaweed derivative that works by modulating the gut microbiota-brain axis.

117MIND diet associated with reduced incidence of Alzheimer's disease.PubMed

Martha Clare Morris, Christy C Tangney, Yamin Wang, et al.
Alzheimers Dement. 2015 Sep;11(9):1007-14. doi: 10.1016/j.jalz.2014.11.009. Epub 2015 Feb 11.
INTRODUCTION: In a previous study, higher concordance to the MIND diet, a hybrid Mediterranean-Dietary Approaches to Stop Hypertension diet, was associated with slower cognitive decline. In this study we related these three dietary patterns to incident Alzheimer's disease (AD). METHODS: We investigated the diet-AD relations in a prospective study of 923 participants, ages 58 to 98 years, followed on average 4.5 years. Diet was assessed by a semiquantitative food frequency questionnaire. RESULTS: In adjusted proportional hazards models, the second (hazards ratio or HR = 0.65, 95% confidence interval or CI 0.44, 0.98) and highest tertiles (HR = 0.47, 95% CI 0.26, 0.76) of MIND diet scores had lower rates of AD versus tertile 1, whereas only the third tertiles of the DASH (HR = 0.61, 95% CI 0.38, 0.97) and Mediterranean (HR = 0.46, 95% CI 0.26, 0.79) diets were associated with lower AD rates. DISCUSSION: High adherence to all three diets may reduce AD risk. Moderate adherence to the MIND diet may also decrease AD risk.

118Preventive Role of L-Carnitine and Balanced Diet in Alzheimer's Disease.PubMed

Alina Kepka, Agnieszka Ochocinska, Małgorzata Borzym-Kluczyk, et al.
Nutrients. 2020 Jul 3;12(7):1987. doi: 10.3390/nu12071987.
The prevention or alleviation of neurodegenerative diseases, including Alzheimer's disease (AD), is a challenge for contemporary health services. The aim of this study was to review the literature on the prevention or alleviation of AD by introducing an appropriate carnitine-rich diet, dietary carnitine supplements and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which contains elements of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. L-carnitine (LC) plays a crucial role in the energetic metabolism of the cell. A properly balanced diet contains a substantial amount of LC as well as essential amino acids and microelements taking part in endogenous carnitine synthesis. In healthy people, carnitine biosynthesis is sufficient to prevent the symptoms of carnitine deficiency. In persons with dysfunction of mitochondria, e.g., with AD connected with extensive degeneration of the brain structures, there are often serious disturbances in the functioning of the whole organism. The Mediterranean diet is characterized by a high consumption of fruits and vegetables, cereals, nuts, olive oil, and seeds as the major source of fats, moderate consumption of fish and poultry, low to moderate consumption of dairy products and alcohol, and low intake of red and processed meat. The introduction of foodstuffs rich in carnitine and the MIND diet or carnitine supplementation of the AD patients may improve their functioning in everyday life.

119Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia.PubMed

Ligia J Dominguez, Nicola Veronese, Laura Vernuccio, et al.
Nutrients. 2021 Nov 15;13(11):4080. doi: 10.3390/nu13114080.
Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.

120Physical activity as a protective factor for dementia and Alzheimer's disease: systematic review, meta-analysis and quality assessment of cohort and case-control studies.PubMed

Paula Iso-Markku, Urho M Kujala, Keegan Knittle, et al.
Br J Sports Med. 2022 Jun;56(12):701-709. doi: 10.1136/bjsports-2021-104981. Epub 2022 Mar 17.
OBJECTIVE: Physical activity (PA) is associated with a decreased incidence of dementia, but much of the evidence comes from short follow-ups prone to reverse causation. This meta-analysis investigates the effect of study length on the association. DESIGN: A systematic review and meta-analysis. Pooled effect sizes, dose-response analysis and funnel plots were used to synthesise the results. DATA SOURCES: CINAHL (last search 19 October 2021), PsycInfo, Scopus, PubMed, Web of Science (21 October 2021) and SPORTDiscus (26 October 2021). ELIGIBILITY CRITERIA: Studies of adults with a prospective follow-up of at least 1 year, a valid cognitive measure or cohort in mid-life at baseline and an estimate of the association between baseline PA and follow-up all-cause dementia, Alzheimer's disease or vascular dementia were included (n=58). RESULTS: PA was associated with a decreased risk of all-cause dementia (pooled relative risk 0.80, 95% CI 0.77 to 0.84, n=257 983), Alzheimer's disease (0.86, 95% CI 0.80 to 0.93, n=128 261) and vascular dementia (0.79, 95% CI 0.66 to 0.95, n=33 870), even in longer follow-ups (≥20 years) for all-cause dementia and Alzheimer's disease. Neither baseline age, follow-up length nor study quality significantly moderated the associations. Dose-response meta-analyses revealed significant linear, spline and quadratic trends within estimates for all-cause dementia incidence, but only a significant spline trend for Alzheimer's disease. Funnel plots showed possible publication bias for all-cause dementia and Alzheimer's disease. CONCLUSION: PA was associated with lower incidence of all-cause dementia and Alzheimer's disease, even in longer follow-ups, supporting PA as a modifiable protective lifestyle factor, even after reducing the effects of reverse causation.

121Healthy Lifestyle and Cognition in Older Adults With Common Neuropathologies of Dementia.PubMed

Klodian Dhana, Puja Agarwal, Bryan D James, et al.
JAMA Neurol. 2024 Mar 1;81(3):233-239. doi: 10.1001/jamaneurol.2023.5491.
IMPORTANCE: A healthy lifestyle is associated with better cognitive functioning in older adults, but whether this association is independent of the accumulation of dementia-related pathologies in the brain is uncertain. OBJECTIVE: To determine the role of postmortem brain pathology, including β-amyloid load, phosphorylated tau tangles, cerebrovascular pathology, and other brain pathologies, in the association between lifestyle and cognition proximate to death. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic study with autopsy data from 1997 to 2022 and up to 24 years of follow-up. Participants included 754 deceased individuals with data on lifestyle factors, cognitive testing proximate to death, and a complete neuropathologic evaluation at the time of these analyses. Data were analyzed from January 2023 to June 2023. EXPOSURES: A healthy lifestyle score was developed based on self-reported factors, including noncurrent smoking, at least 150 minutes of physical activity per week, limiting alcohol consumption, a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet score higher than 7.5, and a late-life cognitive activity score higher than 3.2. The lifestyle score ranges from 0 to 5, with higher scores reflecting a healthier lifestyle. MAIN OUTCOMES AND MEASURES: The global cognitive score was derived from a battery of nineteen standardized tests. Brain pathology measures included β-amyloid load, phosphorylated tau tangles, global Alzheimer disease pathology, vascular brain pathologies, Lewy body, hippocampal sclerosis, and TAR DNA-binding protein 43. RESULTS: Of 586 included decedents, 415 (70.8%) were female, 171 (29.2%) were male, and the mean (SD) age at death was 90.9 (6.0) years. Higher lifestyle score was associated with better global cognitive functioning proximate to death. In the multivariable-adjusted model, a 1-point increase in lifestyle score was associated with 0.216 (SE = 0.036, P < .001) units higher in global cognitive scores. Neither the strength nor the significance of the association changed substantially when common dementia-related brain pathologies were included in the multivariable-adjusted models. The β estimate after controlling for the β-amyloid load was 0.191 (SE = 0.035; P < .001). A higher lifestyle score was associated with lower β-amyloid load in the brain (β = -0.120; SE = 0.041; P = .003), and 11.6% of the lifestyle-cognition association was estimated through β-amyloid load. CONCLUSIONS AND RELEVANCE: This study found that in older adults, a healthy lifestyle may provide a cognitive reserve to maintain cognitive abilities independently of common neuropathologies of dementia.

122Factors Associated with Alzheimer's Disease: An Overview of Reviews.PubMed

M Rochoy, V Rivas, E Chazard, et al.
J Prev Alzheimers Dis. 2019;6(2):121-134. doi: 10.14283/jpad.2019.7.
Alzheimer's disease (AD) is a frequent pathology, with a poor prognosis, for which no curative treatment is available in 2018. AD prevention is an important issue, and is an important research topic. In this manuscript, we have synthesized the literature reviews and meta-analyses relating to modifiable risk factors associated with AD. Smoking, diabetes, high blood pressure, obesity, hypercholesterolemia, physical inactivity, depression, head trauma, heart failure, bleeding and ischemic strokes, sleep apnea syndrome appeared to be associated with an increased risk of AD. In addition to these well-known associations, we highlight here the existence of associated factors less described: hyperhomocysteinemia, hearing loss, essential tremor, occupational exposure to magnetic fields. On the contrary, some oral antidiabetic drugs, education and intellectual activity, a Mediterranean-type diet or using Healthy Diet Indicator, consumption of unsaturated fatty acids seemed to have a protective effect. Better knowledge of risk factors for AD allows for better identification of patients at risk. This may contribute to the emergence of prevention policies to delay or prevent the onset of AD.

123Hypertension-induced cognitive impairment: from pathophysiology to public health.PubMed

Zoltan Ungvari, Peter Toth, Stefano Tarantini, et al.
Nat Rev Nephrol. 2021 Oct;17(10):639-654. doi: 10.1038/s41581-021-00430-6. Epub 2021 Jun 14.
Hypertension affects two-thirds of people aged >60 years and significantly increases the risk of both vascular cognitive impairment and Alzheimer's disease. Hypertension compromises the structural and functional integrity of the cerebral microcirculation, promoting microvascular rarefaction, cerebromicrovascular endothelial dysfunction and neurovascular uncoupling, which impair cerebral blood supply. In addition, hypertension disrupts the blood-brain barrier, promoting neuroinflammation and exacerbation of amyloid pathologies. Ageing is characterized by multifaceted homeostatic dysfunction and impaired cellular stress resilience, which exacerbate the deleterious cerebromicrovascular effects of hypertension. Neuroradiological markers of hypertension-induced cerebral small vessel disease include white matter hyperintensities, lacunar infarcts and microhaemorrhages, all of which are associated with cognitive decline. Use of pharmaceutical and lifestyle interventions that reduce blood pressure, in combination with treatments that promote microvascular health, have the potential to prevent or delay the pathogenesis of vascular cognitive impairment and Alzheimer's disease in patients with hypertension.

124Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison.PubMed

S Son, M Speechley, G Y Zou, et al.
J Prev Alzheimers Dis. 2024;11(5):1490-1499. doi: 10.14283/jpad.2024.105.
BACKGROUND: It has been suggested that up to 40% of dementia cases worldwide are associated with modifiable risk factors; however, these estimates are not known in Canada. Furthermore, sleep disturbances, an emerging factor, has not been incorporated into the life-course model of dementia prevention. OBJECTIVE: To estimate the population impact of 12 modifiable risk factors in Canadian adults including sleep disturbances, by sex and age groups, and to compare with other countries. DESIGN: Cross-sectional analysis of Canadian Longitudinal Study on Aging baseline data. SETTING: Community. PARTICIPANTS: 30,097 adults aged 45 years and older. MEASUREMMENTS: Prevalence and Population Attributable Fractions (PAFs) associated with less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and sleep disturbances. RESULTS: The risk factors with the largest PAF were later life physical inactivity (10.2%; 95% CI, 6.8% to 13%), midlife hearing loss (6.5%; 3.7% to 9.3%), midlife obesity (6.4%; 4.1% to 7.7%), and midlife hypertension (6.2%; 2.7% to 9.3%). The PAF of later life sleep disturbances was 3.0% (95% CI, 1.8% to 3.8%). The 12 risk factors accounted for 51.9% (32.2% to 68.0%) of dementia among men and 52.4% (32.5% to 68.7%) among women. Overall, the combined PAF of all risk factors was 49.2% (31.1% to 64.9%), and it increased with age. CONCLUSION: Nearly up to 50% of dementia cases in Canada are attributable to 12 modifiable risk factors across the lifespan. Canadian risk reduction strategies should prioritize targeting physical inactivity, hearing loss, obesity, and hypertension.

125Insulin Resistance and Diabetes Mellitus in Alzheimer's Disease.PubMed

Jesús Burillo, Patricia Marqués, Beatriz Jiménez, et al.
Cells. 2021 May 18;10(5):1236. doi: 10.3390/cells10051236.
Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer's disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

126Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications.PubMed

Geert Jan Biessels, Florin Despa
Nat Rev Endocrinol. 2018 Oct;14(10):591-604. doi: 10.1038/s41574-018-0048-7.
Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.

127Type 3 Diabetes and Its Role Implications in Alzheimer's Disease.PubMed

Thuy Trang Nguyen, Qui Thanh Hoai Ta, Thi Kim Oanh Nguyen, et al.
Int J Mol Sci. 2020 Apr 30;21(9):3165. doi: 10.3390/ijms21093165.
The exact connection between Alzheimer's disease (AD) and type 2 diabetes is still in debate. However, poorly controlled blood sugar may increase the risk of developing Alzheimer's. This relationship is so strong that some have called Alzheimer's "diabetes of the brain" or "type 3 diabetes (T3D)". Given more recent studies continue to indicate evidence linking T3D with AD, this review aims to demonstrate the relationship between T3D and AD based on the fact that both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are attributed to impaired insulin signaling, and that insulin resistance mediates the dysregulation of bioenergetics and progress to AD. Furthermore, insulin-related therapeutic strategies are suggested to succeed in the development of therapies for AD by slowing down their progressive nature or even halting their future complications.

128Is Alzheimer's disease a type 3 diabetes? A review.PubMed

Jana Janoutová, Ondřej Machaczka, Anna Zatloukalová, et al.
Cent Eur J Public Health. 2022 Sep;30(3):139-143. doi: 10.21101/cejph.a7238.
OBJECTIVES: This is a review article that deals with the question of whether type 2 diabetes is a risk factor for the development of Alzheimer's disease. METHODS: We searched the PubMed database and relevant publications were selected for review. The introduction, which describes the possibilities of how type 2 diabetes can affect the development of Alzheimer's disease, is followed by other questions related to this issue: May on the contrary Alzheimer's disease induce type 2 diabetes? What is a relative risk for type 2 diabetes to induce dementia? How type 2 diabetes influence conversion of mild cognitive impairment to Alzheimer's disease? What is the role of antidiabetic medication? Proposition of term "type 3 diabetes" for Alzheimer's disease. RESULTS: Type 2 diabetes mellitus has been shown to increase the risk for cognitive decline and dementia, such as Alzheimer's disease and vascular dementia. Despite extensive research and numerous publications, the mechanisms underlying these associations remain unclear. CONCLUSIONS: Because of similar molecular and cellular features among type 1 and type 2 diabetes and insulin resistance associated with memory deficit and cognitive decline, some researches proposed the term "type 3 diabetes" for Alzheimer's disease.

129Diabetes and cognitive decline.PubMed

Chiara Bellia, Mauro Lombardo, Marco Meloni, et al.
Adv Clin Chem. 2022;108:37-71. doi: 10.1016/bs.acc.2021.07.006. Epub 2021 Aug 23.
Epidemiologic studies have documented an association between diabetes and increased risk of cognitive decline in the elderly. Based on animal model studies, several mechanisms have been proposed to explain such an association, including central insulin signaling, neurodegeneration, brain amyloidosis, and neuroinflammation. Nevertheless, the exact mechanisms in humans remain poorly defined. It is reasonable, however, that many pathways may be involved in these patients leading to cognitive impairment. A major aim of clinicians is identifying early onset of neurologic signs and symptoms in elderly diabetics to improve quality of life of those with cognitive impairment and reduce costs associated with long-term complications. Several biomarkers have been proposed to identify diabetics at higher risk of developing dementia and diagnose early stage dementia. Although biomarkers of brain amyloidosis, neurodegeneration and synaptic plasticity are commonly used to diagnose dementia, especially Alzheimer disease, their role in diabetes remains unclear. The aim of this review is to explore the molecular mechanisms linking diabetes with cognitive decline and present the most important findings on the clinical use of biomarkers for diagnosing and predicting early cognitive decline in diabetics.

130Diagnostic, Prognostic, and Mechanistic Biomarkers of Diabetes Mellitus-Associated Cognitive Decline.PubMed

Hanan Ehtewish, Abdelilah Arredouani, Omar El-Agnaf
Int J Mol Sci. 2022 May 30;23(11):6144. doi: 10.3390/ijms23116144.
Cognitive dysfunctions such as mild cognitive impairment (MCI), Alzheimer's disease (AD), and other forms of dementia are recognized as common comorbidities of type 2 diabetes mellitus (T2DM). Currently, there are no disease-modifying therapies or definitive clinical diagnostic and prognostic tools for dementia, and the mechanisms underpinning the link between T2DM and cognitive dysfunction remain equivocal. Some of the suggested pathophysiological mechanisms underlying cognitive decline in diabetes patients include hyperglycemia, insulin resistance and altered insulin signaling, neuroinflammation, cerebral microvascular injury, and buildup of cerebral amyloid and tau proteins. Given the skyrocketing global rates of diabetes and neurodegenerative disorders, there is an urgent need to discover novel biomarkers relevant to the co-morbidity of both conditions to guide future diagnostic approaches. This review aims to provide a comprehensive background of the potential risk factors, the identified biomarkers of diabetes-related cognitive decrements, and the underlying processes of diabetes-associated cognitive dysfunction. Aging, poor glycemic control, hypoglycemia and hyperglycemic episodes, depression, and vascular complications are associated with increased risk of dementia. Conclusive research studies that have attempted to find specific biomarkers are limited. However, the most frequent considerations in such investigations are related to C reactive protein, tau protein, brain-derived neurotrophic factor, advanced glycation end products, glycosylated hemoglobin, and adipokines.

131Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease.PubMed

Subbiah Pugazhenthi, Limei Qin, P Hemachandra Reddy
Biochim Biophys Acta Mol Basis Dis. 2017 May;1863(5):1037-1045. doi: 10.1016/j.bbadis.2016.04.017. Epub 2016 May 6.
Cognitive decline in chronic diabetic patients is a less investigated topic. Diabetes and obesity are among the modifiable risk factors for Alzheimer's disease (AD), the most common form of dementia. Studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders. Advanced glycation end products generated by chronic hyperglycemia and their receptor RAGE provide critical links between diabetes and AD. Peripheral inflammation observed in obesity leads to insulin resistance and type 2 diabetes. Although the brain is an immune-privileged organ, cross-talks between peripheral and central inflammation have been reported. Damage to the blood brain barrier (BBB) as seen with aging can lead to infiltration of immune cells into the brain, leading to the exacerbation of central inflammation. Neuroinflammation, which has emerged as an important cause of cognitive dysfunction, could provide a central mechanism for aging-associated ailments. To further add to these injuries, adult neurogenesis that provides neuronal plasticity is also impaired in the diabetic brain. This review discusses these molecular mechanisms that link obesity, diabetes and AD. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

132Imbalanced cholesterol metabolism in Alzheimer's disease.PubMed

Zhao Xue-Shan, Peng Juan, Wu Qi, et al.
Clin Chim Acta. 2016 May 1;456:107-114. doi: 10.1016/j.cca.2016.02.024. Epub 2016 Mar 2.
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease that is mainly caused by β-amyloid accumulation. A large number of studies have shown that elevated cholesterol levels may perform a function in AD pathology, and several cholesterol-related gene polymorphisms are associated with this disease. Although numerous studies have shown the important function of cholesterol in AD pathogenesis and development, the underlying mechanism remains unclear. To further elucidate cholesterol metabolism disorder and AD, we first, review metabolism and regulation of the cholesterol in the brain. Second, we summarize the literature stating that hypercholesterolemia is one of the risk factors of AD. Third, we discuss the main mechanisms of abnormal cholesterol metabolism that increase the risk of AD. Finally, the relationships between AD and apolipoprotein E, PCSK9, and LRP1 are discussed in this article.

133Lipid metabolism in Alzheimer's disease.PubMed

Tian-Bi Zhu, Zhao Zhang, Piao Luo, et al.
Brain Res Bull. 2019 Jan;144:68-74. doi: 10.1016/j.brainresbull.2018.11.012. Epub 2018 Nov 22.
Since the metabolic disorder may be the high risk that contribute to the progress of Alzheimer's disease (AD). Overtaken of High-fat, high-glucose or high-cholesterol diet may hasten the incidence of AD in later life, due to the metabolic dysfunction. But the metabolism of lipid in brain and the exact effect of lipid to brain or to the AD's pathological remain controversial. Here we summarize correlates of lipid metabolism and AD to provide more foundation for the daily nursing of AD sensitive patients.

134Oxysterols and Alzheimer's disease.PubMed

I Björkhem, M Heverin, V Leoni, et al.
Acta Neurol Scand Suppl. 2006;185:43-9. doi: 10.1111/j.1600-0404.2006.00684.x.
There is a clear link between cholesterol turnover and neurodegenerative diseases and hypercholesterolemia is an established risk factor for Alzheimer's disease (AD). The failure to demonstrate a transfer of cholesterol from the circulation into the brain in humans and experimental animals makes it difficult to explain the link between hypercholesterolemia and AD. In contrast to cholesterol itself, side-chain oxidized cholesterol metabolites such as 24S-hydroxycholesterol and 27-hydroxycholesterol are able to pass the blood-brain barrier (BBB). Formation of 24S-hydroxycholesterol is the quantitatively most important mechanism for elimination of cholesterol from the brain and we recently demonstrated a significant net uptake of 27-hydroxycholesterol by the brain from the circulation. We have also shown that patients with AD have increased brain levels of 27-hydroxycholesterol, which may affect the production of beta-amyloid in the brain. The levels of 27-hydroxycholesterol in the circulation are correlated with the levels of cholesterol and the possibility must be considered that the flux of 27-hydroxycholesterol into the brain is the missing link between hypercholesterolemia and Alzheimer's disease. Current knowledge about the role of the two oxysterols for cholesterol homeostasis in the brain as well as their diagnostic potential are reviewed.

135TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.PubMed

Rui-Yang Li, Qi Qin, Han-Chen Yang, et al.
Mol Neurodegener. 2022 Jun 3;17(1):40. doi: 10.1186/s13024-022-00542-y.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

136The projected effect of risk factor reduction on Alzheimer's disease prevalence.PubMed

Deborah E Barnes, Kristine Yaffe
Lancet Neurol. 2011 Sep;10(9):819-28. doi: 10.1016/S1474-4422(11)70072-2. Epub 2011 Jul 19.
At present, about 33·9 million people worldwide have Alzheimer's disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.

137Cognitive reserve and Alzheimer disease.PubMed

Yaakov Stern
Alzheimer Dis Assoc Disord. 2006 Apr-Jun;20(2):112-7. doi: 10.1097/01.wad.0000213815.20177.19.
Epidemiologic evidence suggests that individuals with higher IQ, education, occupational attainment, or participation in leisure activities have a reduced risk of developing Alzheimer disease (AD). The concept of cognitive reserve (CR) posits that individual differences in how tasks are processed provide differential reserve against brain pathology or age-related changes. This may take 2 forms. In neural reserve, preexisting brain networks that are more efficient or have greater capacity may be less susceptible to disruption. In neural compensation, alternate networks may compensate for pathology's disruption of preexisting networks. Imaging studies have begun to identify the neural substrate of CR. Because CR may modulate the clinical expression of AD pathology, it is an important consideration in studies of "preclinical" AD and treatment studies. There is also the possibility that directly enhancing CR may help forestall the diagnosis of AD.

138Learning may provide neuroprotection against dementia.PubMed

F F Youssef, J I Addae
West Indian Med J. 2002 Sep;51(3):143-7.
A number of studies attempting to identify specific risk factors for dementia have noted an inverse relationship between educational background and the likelihood of developing dementia. This idea has been somewhat controversial as educational background can introduce a number of confounding factors that generally affect health and lifestyle. Despite these reservations, there is mounting evidence to support the concept of education (or increased mental activity) producing a functional reserve in the brain, a process that provides some protection against the clinical manifestation of dementia. Long-term potentiation (LTP) is a recognized neural correlate of learning and memory. We have shown recently that LTP reduces the sensitivity of hippocampal neurons to agonists of the neurotransmitter glutamate; additionally, we have reported that LTP protects the neurons from the effects of acute hypoxia. Given that the effect of hypoxia on neurons involves over-stimulation by glutamate, and hypoxia has been implicated in the aetio-pathology of some types of dementia, our observations suggest that LTP has a protective effect on neuronal tissue. Such an interaction offers a physiological basis for the epidemiological evidence that lifelong learning can protect a person from some types of dementia.

139Culture, Ethnicity, and Level of Education in Alzheimer's Disease.PubMed

Mónica Rosselli, Idaly Vélez Uribe, Emily Ahne, et al.
Neurotherapeutics. 2022 Jan;19(1):26-54. doi: 10.1007/s13311-022-01193-z. Epub 2022 Mar 28.
Alzheimer's disease (AD) is the most frequent cause of dementia, where the abnormal accumulation of beta-amyloid (Aβ) and tau lead to neurodegeneration as well as loss of cognitive, behavioral, and functional abilities. The present review analyzes AD from a cross-cultural neuropsychological perspective, looking at differences in culture-associated variables, neuropsychological test performance and biomarkers across ethnic and racial groups. Studies have found significant effects of culture, preferred language, country of origin, race, and ethnicity on cognitive test performance, although the definition of those grouping terms varies across studies. Together, with the substantial underrepresentation of minority groups in research, the inconsistent classification might conduce to an inaccuratte diagnosis that often results from biases in testing procedures that favor the group to which test developers belong. These biases persist even after adjusting for variables related to disadvantageous societal conditions, such as low level of education, unfavorable socioeconomic status, health care access, or psychological stressors. All too frequently, educational level is confounded with culture. Minorities often have lower educational attainment and lower quality of education, causing differences in test results that are then attributed to culture. Higher levels of education are also associated with increased cognitive reserve, a protective factor against cognitive decline in the presence of neurodegeneration. Biomarker research suggests there might be significant differences in specific biomarker profiles for each ethnicity/race in need of accurate cultural definitions to adequately predict risk and disease progression across ethnic/racial groups. Overall, this review highlights the need for diversity in all domains of AD research that lack inclusion and the collection of relevant information from these groups.

140Ageing without dementia: can stimulating psychosocial and lifestyle experiences make a difference?PubMed

Laura Fratiglioni, Anna Marseglia, Serhiy Dekhtyar
Lancet Neurol. 2020 Jun;19(6):533-543. doi: 10.1016/S1474-4422(20)30039-9. Epub 2020 May 26.
In a world with an ageing population, dementia has become an urgent threat to global health and wellbeing. Psychosocial and lifestyle factors, such as higher socioeconomic positions, longer times spent in education, greater occupational complexity, reduced stress at work, and engagement in mental, physical, and social activities, have been hypothesised to supply resilience against dementia. Although questions remain surrounding the role of these factors in the development of dementia, scientific advancements have considerably expanded our understanding of modifiable psychosocial and lifestyle factors and their neuroprotective and compensatory influences over a life course. Evidence from observational studies is robust enough to suggest that stimulating psychosocial and lifestyle factors are protective against dementia. And, although the corresponding evidence from intervention studies is still scarce, public health campaigns promoting psychosocial and lifestyle factors might improve the health and wellbeing of people aged 60 years and older.

141Educational attainment, structural brain reserve and Alzheimer's disease: a Mendelian randomization analysis.PubMed

Aida Seyedsalehi, Varun Warrier, Richard A I Bethlehem, et al.
Brain. 2023 May 2;146(5):2059-2074. doi: 10.1093/brain/awac392.
Higher educational attainment is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer's disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [-0.09 (95% confidence interval -0.15, -0.03)] and white matter hyperintensities volume [-0.14 (95% confidence interval -0.23, -0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically predicted educational attainment with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.

142Education, Occupational Complexity, and Incident Dementia: A COSMIC Collaborative Cohort Study.PubMed

Jinshil Hyun, Charles B Hall, Mindy J Katz, et al.
J Alzheimers Dis. 2022;85(1):179-196. doi: 10.3233/JAD-210627.
BACKGROUND: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia. OBJECTIVE: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts. METHOD: We used data from 10,195 participants (median baseline age = 74.1, range = 58∼103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated failure time model was applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed. RESULT: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28%of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with 'high school completion' or 'above high school' compared to 'middle school completion or below'. CONCLUSION: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course.

143Occupational complexity and cognition in the FINGER multidomain intervention trial.PubMed

Anders Rydström, Alexander Darin-Mattsson, Ingemar Kåreholt, et al.
Alzheimers Dement. 2022 Dec;18(12):2438-2447. doi: 10.1002/alz.12561. Epub 2022 Feb 9.
INTRODUCTION: Lifetime exposure to occupational complexity is linked to late-life cognition, and may affect benefits of preventive interventions. METHODS: In the 2-year multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated, through post hoc analyses (N = 1026), the association of occupational complexity with cognition. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. RESULTS: Higher levels of occupational complexity were associated with better baseline cognition. Measures of occupational complexity had no association with intervention effects on cognition, except for occupational complexity with data, which was associated with the degree of intervention-related gains for executive function. DISCUSSION: In older adults at increased risk for dementia, higher occupational complexity is associated with better cognition. The cognitive benefit of the FINGER intervention did not vary significantly among participants with different levels of occupational complexity. These exploratory findings require further testing in larger studies.

144Association of Occupational Factors and Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis.PubMed

Liang-Yu Huang, He-Ying Hu, Zuo-Teng Wang, et al.
J Alzheimers Dis. 2020;78(1):217-227. doi: 10.3233/JAD-200605.
BACKGROUND: Several existing studies have reported that occupational factors might play an important part in cognitive function with aging. OBJECTIVE: We aim to explore the associations between modifiable occupational factors and risk of dementia or mild cognitive impairment (MCI). METHODS: Adopting random-effect models, this study conducted primary analyses for all occupational factors and subgroup analyses for the effect of occupation type based on prospective cohort and case-control studies searched from PubMed and EMBASE databases up to March 2020. RESULTS: Among the 38,111 identified literatures, 9 studies on occupation type, 4 studies on work complexity, and 30 studies on occupational exposure were included. In terms of occupation type, mental work conferred a 44% reduced risk (95% CI = 0.34-0.94, I² = 85.00%, p < 0.01) for MCI. In terms of work complexity, higher work complexity conferred a 5% reduced risk (95% CI = 0.91-1.00, I² = 57.00%, p < 0.01) for dementia. In terms of occupational exposure, high strain and passive job in the longest-held job conferred a 1.21- and 1.15-fold excess risk (95% CI = 1.05-1.39 I² = 62.00%, p < 0.05; 95% CI = 1.05-1.26 I² = 31.00%, p = 0.23; respectively) of cognitive decline. Besides, magnetic field exposure conferred a 1.26-fold excess risk (95% CI = 1.01-1.57, I² = 69.00%, p < 0.01) for dementia. CONCLUSION: Novel prevention strategies based on occupational factors may hold promise against dementia and MCI.

145Cognitive Reserve, Alzheimer's Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis.PubMed

Monica E Nelson, Dylan J Jester, Andrew J Petkus, et al.
Neuropsychol Rev. 2021 Jun;31(2):233-250. doi: 10.1007/s11065-021-09478-4. Epub 2021 Jan 8.
Cognitive reserve (CR) may reduce the risk of dementia. We summarized the effect of CR on progression to mild cognitive impairment (MCI) or dementia in studies accounting for Alzheimer's disease (AD)-related structural pathology and biomarkers. Literature search was conducted in Web of Science, PubMed, Embase, and PsycINFO. Relevant articles were longitudinal, in English, and investigating MCI or dementia incidence. Meta-analysis was conducted on nine articles, four measuring CR as cognitive residual of neuropathology and five as composite psychosocial proxies (e.g., education). High CR was related to a 47% reduced relative risk of MCI or dementia (pooled-hazard ratio: 0.53 [0.35, 0.81]), with residual-based CR reducing risk by 62% and proxy-based CR by 48%. CR protects against MCI and dementia progression above and beyond the effect of AD-related structural pathology and biomarkers. The finding that proxy-based measures of CR rivaled residual-based measures in terms of effect on dementia incidence underscores the importance of early- and mid-life factors in preventing dementia later.

146Cognitive reserve, cortisol, and Alzheimer's disease biomarkers: A memory clinic study.PubMed

Manasa Shanta Yerramalla, Alexander Darin-Mattsson, Chinedu T Udeh-Momoh, et al.
Alzheimers Dement. 2024 Jul;20(7):4486-4498. doi: 10.1002/alz.13866. Epub 2024 Jun 4.
INTRODUCTION: Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. METHODS: We examined cross-sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD-related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3-year follow-up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. RESULTS: Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD-related biomarkers. DISCUSSION: Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. HIGHLIGHTS: Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients. Cortisol awakening response modified the relation between CR and P-tau, a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted.

147Interaction between Cognitive Reserve and Biomarkers in Alzheimer Disease.PubMed

Elena Carapelle, Ciro Mundi, Tommaso Cassano, et al.
Int J Mol Sci. 2020 Aug 30;21(17):6279. doi: 10.3390/ijms21176279.
Patients with comparable degree of neuropathology could show different cognitive impairments. This could be explained with the concept of cognitive reserve (CR), which includes a passive and an active component. In particular, CR is used to explain the gap between tissue damage and clinical symptoms that has been observed in dementia and, in particular, in patients affected by Alzheimer disease (AD). Different studies confirm brain neuroplasticity. Our preliminary study demonstrated that AD patients with high education showed a CR inversely associated with glucose uptake measured in fluorodeoxyglucose positron emission tomography (FDG-PET), whereas the inverse correlation was observed in AD patients with low education. In other words, our findings suggest that CR compensates the neurodegeneration and allows the maintenance of patients' cognitive performance. Best understanding of the concept of CR could lead to interventions to slow cognitive aging or reduce the risk of dementia.

148Cognitive Training Using a Novel Memory Game on an iPad in Patients with Amnestic Mild Cognitive Impairment (aMCI).PubMed

George Savulich, Thomas Piercy, Chris Fox, et al.
Int J Neuropsychopharmacol. 2017 Aug 1;20(8):624-633. doi: 10.1093/ijnp/pyx040.
BACKGROUND: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties. METHODS: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of amnestic mild cognitive impairment assigned to either the cognitive training (n=21; 8 hours of gameplay over 4 weeks) or control (n=21; clinic visits as usual) groups. RESULTS: Significant time-by-pattern-by-group interactions were found for cognitive performance in terms of the number of errors made and trials needed on the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task (P=.044; P=.027). Significant time-by-group interactions were also found for the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning first trial memory score (P=.002), Mini-Mental State Examination (P=.036), the Brief Visuospatial Memory Test (P=.032), and the Apathy Evaluation Scale (P=.026). Within-group comparisons revealed highly specific effects of cognitive training on episodic memory. The cognitive training group maintained high levels of enjoyment and motivation to continue after each hour of gameplay, with self-confidence and self-rated memory ability improving over time. CONCLUSIONS: Episodic memory robustly improved in the cognitive training group. "Gamified" cognitive training may also enhance visuospatial abilities in patients with amnestic mild cognitive impairment. Gamification maximizes engagement with cognitive training by increasing motivation and could complement pharmacological treatments for amnestic mild cognitive impairment and mild Alzheimer's disease. Larger, more controlled trials are needed to replicate and extend these findings.

149Cholinesterase inhibitors as Alzheimer's therapeutics (Review).PubMed

Kamlesh Sharma
Mol Med Rep. 2019 Aug;20(2):1479-1487. doi: 10.3892/mmr.2019.10374. Epub 2019 Jun 11.
Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally‑derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi‑target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.

150Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease.PubMed

Gabriella Marucci, Michela Buccioni, Diego Dal Ben, et al.
Neuropharmacology. 2021 Jun 1;190:108352. doi: 10.1016/j.neuropharm.2020.108352. Epub 2020 Oct 6.
Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders.

151Donepezil for dementia due to Alzheimer's disease.PubMed

Jacqueline S Birks, Richard J Harvey
Cochrane Database Syst Rev. 2018 Jun 18;6(6):CD001190. doi: 10.1002/14651858.CD001190.pub3.
BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people. One approach to symptomatic treatment of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by blocking the action of the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. This can be done by a group of drugs known as cholinesterase inhibitors. Donepezil is a cholinesterase inhibitor.This review is an updated version of a review first published in 1998. OBJECTIVES: To assess the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease; to compare the efficacy and safety of different doses of donepezil; and to assess the effect of donepezil on healthcare resource use and costs. SEARCH METHODS: We searched Cochrane Dementia and Cognitive Improvement's Specialized Register, MEDLINE, Embase, PsycINFO and a number of other sources on 20 May 2017 to ensure that the search was as comprehensive and up-to-date as possible. In addition, we contacted members of the Donepezil Study Group and Eisai Inc. SELECTION CRITERIA: We included all double-blind, randomised controlled trials in which treatment with donepezil was administered to people with mild, moderate or severe dementia due to Alzheimer's disease for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two different doses of donepezil were compared. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) extracted data on cognitive function, activities of daily living, behavioural symptoms, global clinical state, quality of life, adverse events, deaths and healthcare resource costs. Where appropriate and possible, we estimated pooled treatment effects. We used GRADE methods to assess the quality of the evidence for each outcome. MAIN RESULTS: Thirty studies involving 8257 participants met the inclusion criteria of the review, of which 28 studies reported results in sufficient detail for the meta-analyses. Most studies were of six months' duration or less. Only one small trial lasted 52 weeks. The studies tested mainly donepezil capsules at a dose of 5 mg/day or 10 mg/day. Two studies tested a slow-release oral formulation that delivered 23 mg/day. Participants in 21 studies had mild to moderate disease, in five studies moderate to severe, and in four severe disease. Seventeen studies were industry funded or sponsored, four studies were funded independently of industry and for nine studies there was no information on source of funding.Our main analysis compared the safety and efficacy of donepezil 10 mg/day with placebo at 24 to 26 weeks of treatment. Thirteen studies contributed data from 3396 participants to this analysis. Eleven of these studies were multicentre studies. Seven studies recruited patients with mild to moderate Alzheimer's disease, two with moderate to severe, and four with severe Alzheimer's disease, with a mean age of about 75 years. Almost all evidence was of moderate quality, downgraded due to study limitations.After 26 weeks of treatment, donepezil compared with placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog, range 0 to 70) (mean difference (MD) -2.67, 95% confidence interval (CI) -3.31 to -2.02, 1130 participants, 5 studies), the Mini-Mental State Examination (MMSE) score (MD 1.05, 95% CI 0.73 to 1.37, 1757 participants, 7 studies) and the Severe Impairment Battery (SIB, range 0 to 100) (MD 5.92, 95% CI 4.53 to 7.31, 1348 participants, 5 studies). Donepezil was also associated with better function measured with the Alzheimer's Disease Cooperative Study activities of daily living score for severe Alzheimer's disease (ADCS-ADL-sev) (MD 1.03, 95% CI 0.21 to 1.85, 733 participants, 3 studies). A higher proportion of participants treated with donepezil experienced improvement on the clinician-rated global impression of change scale (odds ratio (OR) 1.92, 95% CI 1.54 to 2.39, 1674 participants, 6 studies). There was no difference between donepezil and placebo for behavioural symptoms measured by the Neuropsychiatric Inventory (NPI) (MD -1.62, 95% CI -3.43 to 0.19, 1035 participants, 4 studies) or by the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scale (MD 0.4, 95% CI -1.28 to 2.08, 194 participants, 1 study). There was also no difference between donepezil and placebo for Quality of Life (QoL) (MD -2.79, 95% CI -8.15 to 2.56, 815 participants, 2 studies).Participants receiving donepezil were more likely to withdraw from the studies before the end of treatment (24% versus 20%, OR 1.25, 95% CI 1.05 to 1.50, 2846 participants, 12 studies) or to experience an adverse event during the studies (72% vs 65%, OR 1.59, 95% 1.31 to 1.95, 2500 participants, 10 studies).There was no evidence of a difference between donepezil and placebo for patient total healthcare resource utilisation.Three studies compared donepezil 10 mg/day to donepezil 5 mg/day over 26 weeks. The 5 mg dose was associated with slightly worse cognitive function on the ADAS-Cog, but not on the MMSE or SIB, with slightly better QoL and with fewer adverse events and withdrawals from treatment. Two studies compared donepezil 10 mg/day to donepezil 23 mg/day. There were no differences on efficacy outcomes, but fewer participants on 10 mg/day experienced adverse events or withdrew from treatment. AUTHORS' CONCLUSIONS: There is moderate-quality evidence that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12 or 24 weeks with donepezil experience small benefits in cognitive function, activities of daily living and clinician-rated global clinical state. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total healthcare resource costs. Benefits on 23 mg/day were no greater than on 10 mg/day, and benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose, but the rates of withdrawal and of adverse events before end of treatment were higher the higher the dose.

152The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review.PubMed

Fangcheng Fan, Hua Liu, Xiaojie Shi, et al.
J Alzheimers Dis. 2022;85(3):1195-1204. doi: 10.3233/JAD-215423.
BACKGROUND: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse. OBJECTIVE: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients. METHODS: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles. RESULTS: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD. CONCLUSION: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

153Cholinesterase inhibitors for Alzheimer's disease.PubMed

J Birks
Cochrane Database Syst Rev. 2006 Jan 25;2006(1):CD005593. doi: 10.1002/14651858.CD005593.
BACKGROUND: Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues. OBJECTIVES: To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. SELECTION CRITERIA: All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. MAIN RESULTS: The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine. AUTHORS' CONCLUSIONS: The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.

154Clinical efficacy and safety of donepezil in the treatment of Alzheimer's disease in Chinese patients.PubMed

Nan Zhang, Marc L Gordon
Clin Interv Aging. 2018 Oct 11;13:1963-1970. doi: 10.2147/CIA.S159920. eCollection 2018.
Donepezil, an acetylcholinesterase inhibitor (AChEI), has been widely used to treat Alzheimer's disease (AD) in China. However, there are few studies focusing on the efficacy and safety of donepezil in Chinese patients. In this review, we discuss 1) the efficacy of donepezil and its comparison with other AChEIs or memantine, 2) the therapeutic responses to donepezil and its influencing factors, and 3) the safety and tolerability of donepezil in Chinese patients with different stages of AD and amnestic mild cognitive impairment, and further compare the similarities and differences of the results between Chinese studies and previous Western studies that predominantly enrolled Caucasian subjects. We include Chinese clinical trials and other well-designed studies investigating donepezil or using donepezil as a positive control, in which the efficacy and/or safety of donepezil have been analyzed. Based on these studies, donepezil has been shown to be effective and safe in Chinese AD patients and may impact AD biomarkers, such as hippocampal atrophy, Aβ, and tau. In addition, the therapeutic response to donepezil may be influenced by apolipoprotein E or cytochrome P450 2D6 polymorphism.

155Genetic variation in N-methyl-D-aspartate receptor subunit NR3A but not NR3B influences susceptibility to Alzheimer's disease.PubMed

Hsin-Ping Liu, Wei-Yong Lin, Shu-Hsiang Liu, et al.
Dement Geriatr Cogn Disord. 2009;28(6):521-7. doi: 10.1159/000254757. Epub 2009 Dec 10.
BACKGROUND: The administration of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has clinically improved the cognitive function of patients with Alzheimer's disease (AD), indicating that a disturbance in glutamatergic transmission might be involved in a predisposition to developing the disease. AIM: The potential association of polymorphisms in NMDA receptor subunits NR3A and NR3B, encoded by the GRIN3A and GRIN3B genes, with AD was investigated. METHODS: We performed a case-control study. Two single nucleotide polymorphisms, 3104 G/A (rs10989563) and 3723 G/A (rs3739722), in the GRIN3A gene and 2 GRIN3B gene polymorphisms, 1210 C/T (rs4807399) and 1730 C/T (rs2240158), were studied. RESULTS: Upon genotyping of the exonic polymorphism in the GRIN3A gene, the G allele was present at a higher rate than the A allele at position 3723 in AD patients compared with normal groups (p < 0.05). Three haplotypes (designated Ht1-3) were identified from these 2 polymorphisms (3104 G/A and 3723 G/A), and the distribution of Ht2 (AG) differed between AD patients and controls (p < 0.05). Additionally, from the 2 GRIN3B gene variants 1210 C/T and 1730 C/T analyzed, no strong association with AD was observed. CONCLUSION: These observations suggest that the genetic variation of the NR3A, but not NR3B, subunit of the NMDA receptor may be a risk factor for AD pathogenesis among the Taiwanese population.

156Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity.PubMed

Olayemi Joseph Olajide, Ismail Tayo Gbadamosi, Emmanuel Olusola Yawson, et al.
J Mol Neurosci. 2021 Jun;71(6):1205-1220. doi: 10.1007/s12031-020-01747-w. Epub 2021 Jan 8.
The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-β (Aβ) accumulation and increased glutamate agonist. While previous studies have shown Aβ-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamate-mediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.

157Role of memantine in the prophylactic treatment of episodic migraine: A systematic review.PubMed

Vinita M Mistry, Paige L Morizio, Marc J Pepin, et al.
Headache. 2021 Sep;61(8):1207-1213. doi: 10.1111/head.14186. Epub 2021 Aug 5.
OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of memantine for the prophylactic treatment of episodic migraine. BACKGROUND: Migraine is a prevalent chronic disease with significant costs to the health care system. Although various prophylactic treatment options are available, these medications have limitations based on efficacy, potential side effects, and patient preference. Memantine is an N-methyl-d-aspartate receptor antagonist used in dementia treatment that may have potential benefit for migraine prophylaxis. METHODS: A systematic search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through December 2020 using the search terms: migraine disorders, migraine, headache disorders, or headache and memantine. Studies selected for the systematic review included prospective, interventional designs and evaluated memantine for prophylaxis of migraine. Animal studies, case reports, abstracts, review articles, protocols without results, and studies not written in English were excluded. Data were extracted using a standardized systematic process and included author, publication date, study design, sample size, patient characteristics, treatment regimen, clinical efficacy outcomes, and adverse drug effects. RESULTS: Four articles were identified for inclusion representing two prospective open-label studies and two randomized, double-blind trials, evaluating 183 patients on memantine overall. A reduction in number of migraine days and headache severity were shown in all four studies in the participants treated with memantine. The most common adverse effects included somnolence, sedation, and nausea, none of which were severe. CONCLUSION: The studies in this review establish that memantine has the potential for use as a treatment option for episodic migraine. Additional long-term studies using an active comparator would be useful to further elucidate its role.

158Treatment of Alzheimer Disease.PubMed

David S Geldmacher
Continuum (Minneap Minn). 2024 Dec 1;30(6):1823-1844. doi: 10.1212/CON.0000000000001503.
OBJECTIVE: Symptom-oriented treatment has been the mainstay of Alzheimer disease (AD) pharmacotherapy for decades. This article reviews the evidence basis for symptomatic treatments for AD and the emerging data on amyloid-lowering therapies with possible disease-slowing effects. LATEST DEVELOPMENT: Amyloid-lowering monoclonal antibody therapies entered clinical use in 2021. In July 2023, lecanemab became the first of these to gain full US Food and Drug Administration (FDA) approval and limited Medicare payment coverage. Donanemab gained similar approval status in July 2024. The approved agents remove amyloid plaque from the brain and appear to slow clinical disease progression but can produce significant adverse events known as amyloid-related imaging abnormalities with cerebral edema or effusion and with cerebral hemorrhages. Extensive safety monitoring is therefore required, including scheduled MRI scans. Also in 2023, brexpiprazole became the first agent specifically approved by the FDA for agitation associated with AD. Suvorexant, an orexin receptor antagonist, previously was approved for the treatment of insomnia in people with mild and moderate AD. ESSENTIAL POINTS: There is robust evidence for the use of acetylcholinesterase inhibitors for patients with mild, moderate, and severe dementia due to AD, including outcomes beyond changes in cognitive screening test scores. More limited studies support the use of memantine in moderate and severe stages. These agents have a primary effect of delaying decline in cognition and function and postponing the emergence of adverse behaviors. Pharmacotherapy for behavioral and psychological symptoms is less predictable, and most clinical trials have had negative results. Anti-amyloid therapies provide the first FDA-approved option to alter AD pathology, but an understanding of overall utility and value to patients remains in its infancy.

159Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release.PubMed

Ildete Luísa Ferreira, Elisabete Ferreiro, Jeannette Schmidt, et al.
Neurobiol Aging. 2015 Feb;36(2):680-92. doi: 10.1016/j.neurobiolaging.2014.09.006. Epub 2014 Sep 6.
Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aβ) peptide. Aβ interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aβ-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aβ, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aβ + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aβ or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aβ or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Aβ. Aβ-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aβ + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Aβ + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aβ-mediated GluN2B-composed NMDARs activation.

160Amyloid β peptide oligomers directly activate NMDA receptors.PubMed

Laura Texidó, Mireia Martín-Satué, Elena Alberdi, et al.
Cell Calcium. 2011 Mar;49(3):184-90. doi: 10.1016/j.ceca.2011.02.001. Epub 2011 Feb 23.
Amyloid beta (Aβ) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unknown. We recently reported that Aβ oligomers cause intracellular Ca(2+) overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether Aβ oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed, Aβ oligomers induced inward non-desensitizing currents that were blocked in the presence of the NMDA receptor antagonists memantine, APV, and MK-801. Intriguingly, the amplitude of the responses to Aβ oligomers was greater for NR1/NR2A heteromers than for NR1/NR2B heteromers expressed in oocytes. Consistent with these findings, we observed that the increase in the cytosolic concentration of Ca(2+) induced by Aβ oligomers in cortical neurons is prevented by AP5, a broad spectrum NMDA receptor antagonist, but slightly attenuated by ifenprodil which blocks receptors with the NR2B subunit. Together, these results indicate that Aβ oligomers directly activate NMDA receptors, particularly those with the NR2A subunit, and further suggest that drugs that attenuate the activity of such receptors may prevent Aβ damage to neurons in Alzheimeŕs disease.

161Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias.PubMed

Nóra Balázs, Dániel Bereczki, Tibor Kovács
Ideggyogy Sz. 2021 Nov 30;74(11-12):379-387. doi: 10.18071/isz.74.0379.
In aging societies, the morbidity and mortality of dementia is increasing at a significant rate, thereby imposing burden on healthcare, economy and the society as well. Patients' and caregivers' quality of life and life expectancy are greatly determined by the early diagnosis and the initiation of available symptomatic treatments. Cholinesterase inhibitors and memantine have been the cornerstones of Alzheimer's therapy for approximately two decades and over the years, more and more experience has been gained on their use in non-Alzheimer's dementias too. The aim of our work was to provide a comprehensive summary about the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer's and non-Alzheimers's dementias.

162Pharmacological treatment of dementia and mild cognitive impairment due to Alzheimer's disease.PubMed

Julius Popp, Sönke Arlt
Curr Opin Psychiatry. 2011 Nov;24(6):556-61. doi: 10.1097/YCO.0b013e32834b7b96.
PURPOSE OF REVIEW: To give an overview of recent developments in pharmacological treatment options of cognitive as well as behavioural and psychological symptoms of dementia (BPSD) associated with Alzheimer's disease (AD) dementia and mild cognitive impairment due to AD (MCI-AD). RECENT FINDINGS: Knowledge about the efficacy and limitations of the antidementive drugs memantine and cholinesterase inhibitors (ChEIs) in different stages of AD is further expanding. The prediction of treatment response to ChEI and assessment of treatment outcome in the individual patient remain unsolved issues. Commonly prescribed antidepressants have recently failed to be beneficial in depressed AD dementia patients. Clinical trials on new disease-modifying drugs have been disappointing so far. SUMMARY: There is an urgent need for more effective treatment options for cognitive symptoms and BPSD in AD dementia and MCI-AD and for disease-modifying drugs to stop the underlying neurodegenerative process. Recently published new research criteria for the diagnosis of AD enlarge the window for the detection of the disease to early, predementia stages and include biomarkers related to the underlying cerebral AD pathology. In future studies, these criteria will hopefully facilitate the identification of effective drugs in early AD stages.

163Tolerability of memantine monotherapy versus adding memantine as combination therapy.PubMed

Estevana Isaac, David Ney, Mijail Serruya, et al.
J Natl Med Assoc. 2022 Jun;114(3):308-313. doi: 10.1016/j.jnma.2022.02.006. Epub 2022 Mar 7.
INTRODUCTION: Prior studies have focused on the clinical efficacy of combination therapy, donepezil and memantine, for patient's diagnosed with Alzheimer's disease. As a result, it has become increasingly routine for providers to prescribe both medications for all-cause neurodegenerative disorders in variable stages of disease. However, the potential adverse drug reactions while described as mild can have serious sequelae in older adults who are already managing the side effects of polypharmacy. This study looks to explore the tolerability of switching cholinesterase inhibitors to memantine monotherapy versus adding memantine as combination therapy for all-cause neurodegenerative disorders. MATERIALS & METHODS: The study is an IRB approved retrospective chart review that includes 175 patients diagnosed with neurocognitive disorders (ICD 10 F00-F03.91 and ICD10 G30-G31.84). Only side effects reported to and recorded by a neurocognitive subspecialist at Jefferson's Memory Disorder Center from 2016 to 2019 were included. RESULTS & DISCUSSION: The odds of a patient reporting side effects on combination therapy in comparison with those patients on memantine monotherapy reporting side effects were significantly greater (OR = 4.33, CI 95% (1.62, 11.52), p = 0.003). In our patient sample, more than 80% of the patients reporting side effects qualified as polypharmacy or excessive polypharmacy (Table 2). As a result, variable polypharmacy (p = 0.047) was statistically significant in the in a binary logistic regression model for predicting outcomes for patients on combination therapy (Table 3). Therefore, as a patient progresses to moderate-severe stages of disease, we recommend switching CI monotherapy to memantine monotherapy as opposed to adding memantine as combination therapy for those patients on more than 10 other medications to increase tolerability. Given the limitations of a smaller sample size, variables such as severity of disease, renal and liver impairment as well as medication dosing were not significant predictors (Table 3) for those reporting side effects on combination therapy.

164Alzheimer Disease: Treatment of Cognitive and Functional Symptoms.PubMed

Ecler Ercole Jaqua, Mai-Linh N Tran, Mary Hanna
Am Fam Physician. 2024 Sep;110(3):281-293.
Alzheimer disease is a progressive, neurodegenerative disorder characterized by the accumulation of amyloid beta plaques and hyperphosphorylated tau proteins. Alzheimer disease affects cognitive function, leading to memory loss and impairment in activities of daily living. Approximately 6.9 million people in the United States 65 years and older live with Alzheimer disease, a number expected to double by 2060. Although there is no cure for Alzheimer disease, treatments are available to manage symptoms. Tools such as the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., criteria aid in identifying major neurocognitive disorders. The evaluation involves a comprehensive medical history, cognitive examinations, and collateral information. Nonpharmacologic interventions focus on psychosocial approaches, with music, sensory stimulation, and validation therapies showing some evidence of reducing responsive behaviors. Pharmacologic management, such as acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and the N-methyl-d-aspartate receptor antagonist memantine, targets symptom relief and disease progression. Vitamin E does not improve cognition but may mitigate functional decline. Brexpiprazole has been approved in the United States for treating agitation associated with Alzheimer disease. Anti-amyloid monoclonal antibody treatments are approved for mild cognitive impairment and mild Alzheimer disease, but they are controversial and safety concerns exist. Ineffective therapies include ginkgo biloba, nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins.

165Lecanemab (BAN2401): an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease.PubMed

Grace E Vitek, Boris Decourt, Marwan N Sabbagh
Expert Opin Investig Drugs. 2023 Feb;32(2):89-94. doi: 10.1080/13543784.2023.2178414. Epub 2023 Feb 28.
INTRODUCTION: Nearly a dozen monoclonal antibodies (mAbs) directed against beta-amyloid (Aβ) have been developed for the treatment of Alzheimer disease (AD), and most of these mAbs are undergoing clinical trials. Newer mAbs have targeted more specific Aβ types. Lecanemab Eisai has a high affinity for large and soluble Aβ protofibrils. Data from phase 2 clinical trials have suggested the possibility of a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs). Lecanemab is currently being studied in phase 3 trials. AREAS COVERED: This article briefly reviews mAbs that target Aβ in AD and discusses the biology, mechanism of action, and targets of lecanemab. EXPERT OPINION: mAbs that target Aβ are an important focus of therapeutic development for AD, with several soon to be considered for US Food and Drug Administration approval. The experience of aducanumab informs the development of other mAbs, such as lecanemab. One consideration is the conformation of Aβ targets. Targeting monomeric species has not resulted in robust clinical efficacy, whereas targeting Aβ in the form of oligomers, protofibrils, and plaques has shown evidence of slowing clinical decline. Another consideration is that mAbs will require safety monitoring for ARIAs.

166Antibody-Mediated Clearance of Brain Amyloid-β: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aβ Antibodies, and Downstream Effects.PubMed

David A Loeffler
J Alzheimers Dis Rep. 2023 Aug 14;7(1):873-899. doi: 10.3233/ADR-230025. eCollection 2023.
Immunotherapeutic efforts to slow the clinical progression of Alzheimer's disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab's phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies.

167Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer's Disease.PubMed

Jeffrey Cummings, Amanda M Leisgang Osse, Davis Cammann, et al.
BioDrugs. 2024 Jan;38(1):5-22. doi: 10.1007/s40259-023-00633-2. Epub 2023 Nov 13.
Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who have proven β-amyloid pathology (Aβ). One of these, lecanemab, has subsequently received full approval and other monoclonal antibodies are poised for positive review and approval. Anti-amyloid mAbs share the feature of producing a marked reduction in total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing of cognitive decline have achieved a reduction in measurable plaque Aβ in the range of 15-25 centiloids; trials of agents that did not reach this threshold were not associated with cognitive benefit. mAbs have differences in terms of titration schedules, MRI monitoring schedules for amyloid-related imaging abnormalities (ARIA), and continuing versus interrupted therapy. The approximate 30% slowing of decline observed with mAbs is clinically meaningful in terms of extended cognitive integrity and delay of onset of the more severe dementia phases of Alzheimer's disease. Approval of these agents initiates a new era in Alzheimer's disease therapeutics with disease-modifying properties. Further advances are needed, i.e. greater efficacy, improved safety, enhanced convenience, and better understanding of ill-understood observations such as brain volume loss.

168Chemical-Driven Amyloid Clearance for Therapeutics and Diagnostics of Alzheimer's Disease.PubMed

Hye Yun Kim, YoungSoo Kim
Acc Chem Res. 2024 Nov 19;57(22):3266-3276. doi: 10.1021/acs.accounts.4c00458. Epub 2024 Nov 4.
A century ago, German neurologist Alois Alzheimer documented the first case of Alzheimer's disease (AD), illuminating cognitive impairments associated with the presence of abnormal protein clusters, including amyloid plaques and tau tangles, within the brain. In a typical physiological state, the equilibrium of amyloid-β (Aβ) levels is maintained, but aging can precipitate disruptions in the homeostasis of Aβ due to its overproduction, impaired clearance, and other factors, ultimately leading to its accumulation. Although the link between Aβ aggregates and neurodegeneration has long made Aβ a promising target for AD, decades without successful drug development targeting Aβ have generated skepticism regarding the efficacy of this strategy for AD therapy. However, recent approvals of anti-Aβ antibody drugs by the FDA, including aducanumab (Aduhelm), lecanemab (Leqembi), and donanemab (Kisunla), have prompted a re-evaluation of this perspective. These therapies have demonstrated efficacy in reducing brain Aβ levels, thereby decelerating disease progression and reaffirming Aβ as a key target. Despite advancements, immunotherapies are accompanied by considerable disadvantages, including adverse effects, high costs, and cumbersome administration. To address these limitations, our research has focused on developing small molecules that can mitigate the challenges of antibody treatments while offering practical and accessible options. We identified 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid (EPPS) as a promising compound that significantly reduces aggregated Aβ in the brain and enhances behavior in AD rodent models. Following administration, EPPS penetrates the blood-brain barrier (BBB) and binds to toxic Aβ aggregates, subsequently breaking them down into nontoxic monomers. This leads to two significant outcomes: a reduction of Aβ aggregates in the brain and a subsequent increase in Aβ monomers in blood. The monomeric Aβ, unlike its aggregated form, can now traverse the BBB and enter the bloodstream. This mechanism provides an innovative approach to AD treatment and diagnosis. By detaching cerebral Aβ aggregates, EPPS facilitates Aβ clearance and addresses a key pathological feature of AD. Concurrently, the increase in blood Aβ levels offers a potential biomarker for monitoring treatment efficacy and disease progression, thereby revolutionizing both AD treatment and diagnosis. Investigating the detailed mode of action of drug candidates requires structural information about a target protein. Unfortunately, the unstable and heterogeneous nature of Aβ aggregates, which form larger clusters, complicates the identification of these structures. Therefore, we developed new tools for screening small molecules by immobilizing monomeric Aβ and its fragments on plates. This allows us not only to identify novel compounds that target Aβ but also to elucidate their mechanisms of action, enabling the development of Aβ-targeting therapeutic avenues in AD. We believe that our work on chemical-driven amyloid clearance through small molecules represents an advance in AD research, offering chemical diversity and straightforward, economical development processes. In clinical practice, we anticipate that these findings will contribute to the development of patient-friendly therapeutic and diagnostic interventions, including self-administered and orally available options, thereby enhancing disease management and overall quality of life for individuals with AD. Furthermore, this research extends beyond AD, potentially offering insights into other neurodegenerative diseases characterized by protein aggregation.

169Anti-amyloid antibody treatments for Alzheimer's disease.PubMed

Robert Perneczky, Geert Dom, Andrew Chan, et al.
Eur J Neurol. 2024 Feb;31(2):e16049. doi: 10.1111/ene.16049. Epub 2023 Sep 11.
Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid-β. This is a joint statement of the European Association of Neurology and the European Psychiatric Association. After numerous unsuccessful endeavors to create a disease-modifying therapy for Alzheimer's disease, substantial and consistent evidence supporting the clinical effectiveness of monoclonal antibodies aimed at amyloid-β is finally emerging. The latest trials not only achieved their primary objective of slowing the progression of the disease over several months but also demonstrated positive secondary clinical outcomes and a decrease in amyloid-β levels as observed through positron emission tomography scans. Taken as a whole, these findings mark a significant breakthrough by substantiating that reducing amyloid-β yields tangible clinical benefits, beyond mere changes in biomarkers. Concurrently, the regular utilization of the new generation of drugs will determine whether statistical efficacy translates into clinically meaningful improvements. This may well signify the dawning of a new era in the development of drugs for Alzheimer's disease.

170Viewpoint: Clinicians' Perspectives on How Disease Modifying Drugs for Alzheimer's Disease Impact Specialty Care.PubMed

S Gauthier, Z Ismail, Z Goodarzi, et al.
J Prev Alzheimers Dis. 2023;10(3):339-341. doi: 10.14283/jpad.2023.72.
Clinicians specialized in the diagnosis and management of persons living with early-stage Alzheimer's disease need to enable access, for those meeting criteria, to the new class of disease modifying drugs (DMDs). These drugs act on amyloid β42 and delay progression of symptoms. Thus, there will be interest from patients and families. Over the short term, the use of antibodies administered intravenously with serial MRIs to detect amyloid-related imaging abnormalities (ARIA) may require participation in structured phase 4 studies or in registries with third party funding for support staff and MRI scans. In the mid term, the availability of oral anti-amyloid therapy, likely with lower risk of ARIA, may transform clinical practice to a model of screening suitable patients using plasma biomarkers, with a subsequent rapid referral to a specialized memory clinic. Eventually, the biological profile of patients for amyloid, tau, and inflammation will determine which type of DMD to use. We are optimistic that clinicians will gain confidence with the use DMDs and answer the increasing needs of our aging population.

171Eligibility Rates among Racially and Ethnically Diverse US Participants in Phase 2 and Phase 3 Placebo-Controlled, Double-Blind, Randomized Trials of Lecanemab and Elenbecestat in Early Alzheimer Disease.PubMed

Joshua D Grill, Charlene Flournoy, Shobha Dhadda, et al.
Ann Neurol. 2024 Feb;95(2):288-298. doi: 10.1002/ana.26819. Epub 2023 Oct 25.
OBJECTIVE: Many factors contribute to inadequate diversity in Alzheimer disease (AD) clinical trials. We evaluated eligibility rates among racial and ethnic groups at US sites in large global multisite trials in early AD. METHODS: Using screening data from 4 randomized, double-blind, placebo-controlled clinical trials in early AD, we assessed rates of eligibility among racial and ethnic groups controlling for other demographic covariates. Each trial incorporated positron emission tomography and/or cerebrospinal fluid to evaluate brain amyloid pathology, as well as typical eligibility criteria used in early AD trials. RESULTS: Across the trials, 10,804 US participants were screened: 193 (2%) were of Hispanic ethnicity and Black race, 2,624 (25%) were of Hispanic ethnicity and White race, 118 (1%) were of non-Hispanic ethnicity (NH) and Asian race, 696 (7%) were of NH ethnicity and Black race, and 7,017 (65%) were of NH ethnicity and White race. Data from 156 participants who did not fit into these categories were excluded. Accounting for age, sex, and trial and using NH White participants as a reference group, we observed higher probabilities of ineligibility for amyloid biomarker criteria among Hispanic Black (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 2.11-4.88), Hispanic White (OR = 4.15, 95% CI = 3.58-4.83), NH Asian (OR = 2.35, 95% CI = 1.23-4.55), and NH Black (OR = 3.75, 95% CI = 2.80-5.06) participants. INTERPRETATION: Differential eligibility may contribute to underrepresentation of some minoritized racial and ethnic groups in early AD trials. Amyloid biomarker eligibility is a requirement to confirm the diagnosis of AD and for treatment with amyloid-lowering drugs and differed among racial and ethnic groups. ANN NEUROL 2024;95:288-298.

172Anti-Amyloid Therapy, AD, and ARIA: Untangling the Role of CAA.PubMed

Mo-Kyung Sin, Edward Zamrini, Ali Ahmed, et al.
J Clin Med. 2023 Oct 27;12(21):6792. doi: 10.3390/jcm12216792.
Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.

173Plasma Biomarkers for Cerebral Amyloid Angiopathy and Implications for Amyloid-Related Imaging Abnormalities: A Comprehensive Review.PubMed

Mo-Kyung Sin, Jeffrey L Dage, Kwangsik Nho, et al.
J Clin Med. 2025 Feb 7;14(4):1070. doi: 10.3390/jcm14041070.
Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer's disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity.

174A novel biochemical analysis for ApoE4 quantification in plasma and discrimination of homozygous and heterozygous APOE ε4 carriers.PubMed

Andrés Rodríguez, Olga Calero, Sergio Veiga, et al.
Alzheimers Res Ther. 2025 Jul 15;17(1):163. doi: 10.1186/s13195-025-01811-w.
BACKGROUND: The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with increased risk of amyloid-related imaging abnormalities (ARIA) during anti-amyloid therapy. Accurate identification of ε4 carriers, particularly APOE ε4/ε4 individuals, is clinically relevant. This study outlines the development and validation of e4Quant, a novel turbidimetric assay for quantifying plasma ApoE4 as a non-genetic alternative to APOE genotyping. METHODS: The e4Quant test utilizes a proprietary particle-enhanced immunoturbidimetry method, employing an isoform-specific anti-ApoE4 antibody on standard chemistry analyzers. Plasma samples from 160 individuals of known APOE genotype (35 APOE ε4/ε4 homozygotes, 115 APOE ε4 heterozygotes, and 10 APOE ε4 non-carriers) were analyzed for ApoE4 and total ApoE levels. The test's discriminatory performance was assessed by ROC analysis and two-threshold classification algorithms. RESULTS: ApoE4 levels ascertained by the e4Quant test exhibited clear genotype-dependent stratification. ROC analysis indicated 100% sensitivity and specificity in distinguishing APOE ε4 carriers from non-carriers, and 88.6% sensitivity and 90.4% specificity for discriminating homozygous from heterozygous carriers. Normalizing ApoE4 to total ApoE improved classification (sensitivity 94.3%, specificity 93.9%). A combined ratio-plus-concentration approach further enhanced discrimination (sensitivity 91.4%, specificity 100%). Three ε4 homozygous samples with low ApoE4/total ApoE ratios were misclassified. DISCUSSION: The e4Quant assay offers a rapid, cost-effective, and highly accurate biochemical alternative to APOE genotyping, suitable for clinical and research settings, particularly in assessing AD risk and optimizing anti-amyloid therapeutic strategies. One subgroup of APOE ε4/ε4 subjects had unexpectedly low ApoE4 levels, raising questions about potential biological heterogeneity and its impact on Alzheimer's disease biology. CONCLUSION: The e4Quant assay is a novel alternative for genotyping to determine APOE ε4 carrier status, while also providing quantitative measurements of ApoE4 levels. Its high diagnostic accuracy, ease of use in standard clinical laboratories, and potential utility for personalized medicine in AD treatment highlight its translational value. Further studies are warranted to investigate the clinical significance of APOE ε4 expression variability and its impact on disease progression and treatment response.

175Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.PubMed

Susan M Landau, JiaQie Lee, Alice Murphy, et al.
Alzheimers Dement. 2024 Mar;20(3):2113-2127. doi: 10.1002/alz.13609. Epub 2024 Jan 19.
INTRODUCTION: Abnormal amyloid-beta (Aβ) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aβ+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aβ+ unimpaired and 42% of impaired Aβ+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aβ- and tau-modifying therapies.

176Brain lymphatic drainage pathways, deep cervical lymphatic surgery, and current insights: A systematic review.PubMed

Theodore Lahmar, Francois Thuau, Gaelle Pinard, et al.
J Prev Alzheimers Dis. 2025 Aug 27:100335. doi: 10.1016/j.tjpad.2025.100335.
The discovery of the glymphatic system and the later rediscovery of the meningeal lymphatic network have significantly changed our understanding of central nervous system (CNS) waste clearance. Aging is linked to a gradual decline in these clearance pathways, resulting in waste buildup. As a result, therapeutic strategies targeting cerebral lymphatic function have garnered growing interest, with lymphatic surgery emerging as a promising option. We conducted a review until July 2025, providing an overview of the potential of lymphatic surgical techniques to enhance CNS metabolic waste clearance pathways as a therapeutic approach for brain lymphatic system disorders. Currently available data are limited, nine publications addressing this approach. These studies explore an innovative technique involving lymphatico-venous anastomoses (LVA) targeting deep cervical lymphatic vessels to promote clearance for the treatment of Alzheimer's or Parkinson's diseases. Cerebral lymphatic drainage is critical for effective brain waste elimination such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to neurodegenerative diseases. Viewing these lymphatic dysfunctions as a form of "cerebral lymphedema," LVA, already used in treating peripheral lymphedema, shows potential as a therapeutic approach. Although clinical evidence is still limited, lymphatic supermicrosurgery presents promising therapeutic possibilities for neurodegenerative diseases and other conditions related to impaired CNS lymphatic outflow.

177A Novel Microsurgical Model of Cervical Lymph Node-to-Vein Anastomosis (LNVA) for Studying Brain Lymphatic Outflow.PubMed

Renpeng Fang, Lei Jin, Hongrui Lu, et al.
J Craniofac Surg. 2025 Sep 1;36(6):2160-2163. doi: 10.1097/SCS.0000000000011535. Epub 2025 Jun 18.
BACKGROUND: Cervical lymphaticovenous bypass has recently emerged as an innovative surgical approach to enhance brain lymphatic clearance for the treatment of Alzheimer disease (AD). Although early clinical findings are promising, the absence of a reproducible preclinical model has hindered mechanistic investigations and translational advancements. OBJECTIVE: This study aimed to establish the first rat model for cervical LVA, addressing technical challenges and providing a standardized platform for preclinical research on lymphatic clearance and its role in neurodegeneration. METHODS: Rats underwent bilateral cervical LNVA using high-magnification supermicrosurgical techniques. After identification of the deep cervical lymph nodes, end-to-side lymph node-to-venous anastomosis was performed. Anastomotic patency was confirmed intraoperatively by direct visualization without leakage. Indocyanine green (ICG) lymphangiography, performed through nasal administration, demonstrated fluorescence drainage into the external jugular vein. RESULTS: With progressive refinement of microsurgical skills and improved anatomic familiarity, procedural stability was achieved. In the final cohort of 5 rats, all LVA procedures resulted in successful anastomotic patency. CONCLUSION: This study is the first to establish a rat model of cervical deep lymph node-venous anastomosis (LNVA), offering a novel microsurgical platform with dual value. On one hand, it serves as a technically demanding and reproducible model for advanced training in plastic and lymphatic surgery. On the other, it provides a structurally precise, gain-of-function approach for targeted intervention of the deep cervical lymph nodes-an anatomic hub increasingly implicated in brain lymphatic clearance and neurodegeneration. As such, this model may contribute meaningfully to future mechanistic studies on glymphatic function and its modulation.

178Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease.PubMed

Bruno Fonseca-Santos, Maria Palmira Daflon Gremião, Marlus Chorilli
Int J Nanomedicine. 2015 Aug 4;10:4981-5003. doi: 10.2147/IJN.S87148. eCollection 2015.
Alzheimer's disease is a neurological disorder that results in cognitive and behavioral impairment. Conventional treatment strategies, such as acetylcholinesterase inhibitor drugs, often fail due to their poor solubility, lower bioavailability, and ineffective ability to cross the blood-brain barrier. Nanotechnological treatment methods, which involve the design, characterization, production, and application of nanoscale drug delivery systems, have been employed to optimize therapeutics. These nanotechnologies include polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, and liquid crystals. Each of these are promising tools for the delivery of therapeutic devices to the brain via various routes of administration, particularly the intranasal route. The objective of this study is to present a systematic review of nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease.

179Alzheimer's disease: A matter of blood-brain barrier dysfunction?PubMed

Axel Montagne, Zhen Zhao, Berislav V Zlokovic
J Exp Med. 2017 Nov 6;214(11):3151-3169. doi: 10.1084/jem.20171406. Epub 2017 Oct 23.
The blood-brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer's disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

180A review on advances of treatment modalities for Alzheimer's disease.PubMed

Ewen Se Thoe, Ayesha Fauzi, Yin Quan Tang, et al.
Life Sci. 2021 Jul 1;276:119129. doi: 10.1016/j.lfs.2021.119129. Epub 2021 Jan 27.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is mainly characterized by progressive impairment in cognition, emotion, language and memory in older population. Considering the impact of AD, formulations of pharmaceutical drugs and cholinesterase inhibitors have been widely propagated, receiving endorsement by FDA as a form of AD treatment. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis but merely targeting the symptoms so as to improve a patient's cognitive outcome. Hence, a search for better disease-modifying alternatives is put into motion. Having a clear understanding of the neuroprotective mechanisms and diverse properties undertaken by specific genes, antibodies and nanoparticles is central towards designing novel therapeutic agents. In this review, we provide a brief introduction on the background of Alzheimer's disease, the biology of blood-brain barrier, along with the potentials and drawbacks associated with current therapeutic treatment avenues pertaining to gene therapy, immunotherapy and nanotherapy for better diagnosis and management of Alzheimer's disease.

181Latest Perspectives on Alzheimer's Disease Treatment: The Role of Blood-Brain Barrier and Antioxidant-Based Drug Delivery Systems.PubMed

Bianca Sânziana Daraban, Andrei Sabin Popa, Miruna S Stan
Molecules. 2024 Aug 27;29(17):4056. doi: 10.3390/molecules29174056.
There has been a growing interest recently in exploring the role of the blood-brain barrier (BBB) in the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline and memory loss that affects millions of people worldwide. Research has shown that the BBB plays a crucial role in regulating the entry of therapeutics into the brain. Also, the potential benefits of using antioxidant molecules for drug delivery were highlighted in Alzheimer's treatment to enhance the therapeutic efficacy and reduce oxidative stress in affected patients. Antioxidant-based nanomedicine shows promise for treating AD by effectively crossing the BBB and targeting neuroinflammation, potentially slowing disease progression and improving cognitive function. Therefore, new drug delivery systems are being developed to overcome the BBB and improve the delivery of therapeutics to the brain, ultimately improving treatment outcomes for AD patients. In this context, the present review provides an in-depth analysis of recent advancements in AD treatment strategies, such as silica nanoparticles loaded with curcumin, selenium nanoparticles loaded with resveratrol, and many others, focusing on the critical role of the BBB and the use of antioxidant-based drug delivery systems.

182Nanomedicine against Alzheimer's and Parkinson's Disease.PubMed

Ankit Tandon, Sangh J Singh, Rajnish K Chaturvedi
Curr Pharm Des. 2021;27(12):1507-1545. doi: 10.2174/1381612826666201021140904.
Alzheimer's and Parkinson's are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.

183Liposome delivery systems for the treatment of Alzheimer's disease.PubMed

Callum Ross, Mark Taylor, Nigel Fullwood, et al.
Int J Nanomedicine. 2018 Dec 12;13:8507-8522. doi: 10.2147/IJN.S183117. eCollection 2018.
Alzheimer's disease (AD) will affect around 115 million people worldwide by the year 2050. It is associated with the accumulation of misfolded and aggregated proteins (β-amyloid and tau) in the senile plaques and neurofibrillary tangles found in the brain. Currently available drugs for AD only temporarily alleviate symptoms and do not slow the inevitable progression of this disease. New drugs are required that act on key pathologies in order to arrest or reverse cognitive decline. However, there has been a spectacular failure rate in clinical trials of conventional small molecule drugs or biological agents. Targeted nanoliposomes represent a viable and promising drug delivery system for AD that have not yet reached clinical trials. They are biocompatible, highly flexible, and have the potential to carry many different types of therapeutic molecules across the blood-brain barrier (BBB) and into brain cells. They can be tailored to extend blood circulation time and can be directed against individual or multiple pathological targets. Modifications so far have included the use of brain-penetrating peptides, together with Aβ-targeting ligands, such as phosphatidic acid, curcumin, and a retro-inverted peptide that inhibits Aβ aggregation. Combining several modifications together into multifunctional liposomes is currently a research area of great interest. This review focuses on recent liposomal approaches to AD therapy, including mechanisms involved in facilitating their passage across the BBB, and the evaluation of new therapeutic agents for blocking Aβ and/or tau aggregation.

184Therapeutic Potential of Nanomedicine in Management of Alzheimer's Disease and Glioma.PubMed

Firoz Anwar, Fahad A Al-Abbasi, Salma Naqvi, et al.
Int J Nanomedicine. 2023 May 22;18:2737-2756. doi: 10.2147/IJN.S405454. eCollection 2023.
Neoplasm (Glioblastoma) and Alzheimer's disease (AD) comprise two of the most chronic psychological ailments. Glioblastoma is one of the aggressive and prevalent malignant diseases characterized by rapid growth and invasion resulting from cell migration and degradation of extracellular matrix. While the latter is characterized by extracellular plaques of amyloid and intracellular tangles of tau proteins. Both possess a high degree of resistance to treatment owing to the restricted transport of corresponding drugs to the brain protected by the blood-brain barrier (BBB). Development of optimized therapies using advanced technologies is a great need of today. One such approach is the designing of nanoparticles (NPs) to facilitate the drug delivery at the target site. The present article elaborates the advances in nanomedicines in treatment of both AD as well as Gliomas. The intention of this review is to provide an overview of different types of NPs with their physical properties emphasizing their importance in traversing the BBB and hitting the target site. Further, we discuss the therapeutic applications of these NPs along with their specific targets. Multiple overlapping factors with a common pathway in development of AD and Glioblastoma are discussed in details that will assist the readers in developing the conceptual approach to target the NP for an aging population in the given circumstances with limitations of currently designed NPs, and the challenges to meet and the future perspectives.

185Nanomedicine for the Treatment of Alzheimer's Disease.PubMed

Beatrice Formicola, Alysia Cox, Roberta Dal Magro, et al.
J Biomed Nanotechnol. 2019 Oct 1;15(10):1997-2024. doi: 10.1166/jbn.2019.2837.
Alzheimer's disease affects millions of people worldwide and this figure is continuously increasing. Currently, there is no resolutive cure for this disorder, but a valid contribution could be provided by nanomedicine, utilizing multi-functionalized nanodevices as drug vehicles with additional features of specific brain targeting. Nanomedicine may represent also a practicable strategy for the pharmaceutical industry that moved from small MW pharmaceuticals to larger biologicals, such as antibodies and nucleotides, as the next generation of drugs, leading to the challenge of effective drug delivery. This review provides a survey on the nano-based strategies for Alzheimer's disease diagnosis and treatment, aiming at enhancing the passage of candidate pharmaceuticals across the BBB, and at supporting the evaluation of new therapeutic agents targeting this disease.

186Blood-brain barrier penetrating neprilysin degrades monomeric amyloid-beta in a mouse model of Alzheimer's disease.PubMed

Fadi Rofo, Nicole G Metzendorf, Cristina Saubi, et al.
Alzheimers Res Ther. 2022 Dec 5;14(1):180. doi: 10.1186/s13195-022-01132-2.
BACKGROUND: Aggregation of the amyloid-β (Aβ) peptide in the brain is one of the key pathological events in Alzheimer's disease (AD). Reducing Aβ levels in the brain by enhancing its degradation is one possible strategy to develop new therapies for AD. Neprilysin (NEP) is a membrane-bound metallopeptidase and one of the major Aβ-degrading enzymes. The secreted soluble form of NEP (sNEP) has been previously suggested as a potential protein-therapy degrading Aβ in AD. However, similar to other large molecules, peripherally administered sNEP is unable to reach the brain due to the presence of the blood-brain barrier (BBB). METHODS: To provide transcytosis across the BBB, we recombinantly fused the TfR binding moiety (scFv8D3) to either sNEP or a previously described variant of NEP (muNEP) suggested to have higher degradation efficiency of Aβ compared to other NEP substrates, but not per se to degrade Aβ more efficiently. To provide long blood half-life, an Fc-based antibody fragment (scFc) was added to the designs, forming sNEP-scFc-scFv8D3 and muNEP-scFc-scFv8D3. The ability of the mentioned recombinant proteins to degrade Aβ was first evaluated in vitro using synthetic Aβ peptides followed by sandwich ELISA. For the in vivo studies, a single injection of 125-iodine-labelled sNEP-scFc-scFv8D3 and muNEP-scFc-scFv8D3 was intravenously administered to a tg-ArcSwe mouse model of AD, using scFc-scFv8D3 protein that lacks NEP as a negative control. Different ELISA setups were applied to quantify Aβ concentration of different conformations, both in brain tissues and blood samples. RESULTS: When tested in vitro, sNEP-scFc-scFv8D3 retained sNEP enzymatic activity in degrading Aβ and both constructs efficiently degraded arctic Aβ. When intravenously injected, sNEP-scFc-scFv8D3 demonstrated 20 times higher brain uptake compared to sNEP. Both scFv8D3-fused NEP proteins significantly reduced aggregated Aβ levels in the blood of tg-ArcSwe mice, a transgenic mouse model of AD, following a single intravenous injection. In the brain, monomeric and oligomeric Aβ were significantly reduced. Both scFv8D3-fused NEP proteins displayed a fast clearance from the brain. CONCLUSION: A one-time injection of a BBB-penetrating NEP shows the potential to reduce, the likely most toxic, Aβ oligomers in the brain in addition to monomers. Also, Aβ aggregates in the blood were reduced.

187[Behavioral and psychological symptoms of dementia (BPSD): how to proceed].PubMed

Egemen Savaskan
Ther Umsch. 2015 Apr;72(4):255-60. doi: 10.1024/0040-5930/a000673.
The prevalence of the behavioral and psychological symptoms of dementia (BPSD) is very high in dementia patients. Alterations in multiple neurotransmitter systems are involved in the pathogenesis of BPSD. These symptoms complicate the therapy and outcome. Because of multimorbidity and polpharmacy the therapy of BPSD is difficult and needs continuous clinical observation of the patients. Non-pharmacological interventions must be the first choice of therapy before medication and may accompany the pharmacological treatment. Several non-pharmacological interventions are available and summarized in the following therapy recommendations of the Swiss medical societies. Pharmacological interventions are often accompanied by severe adverse events in dementia patients. Their use must be limited in time and quantity. A critical survey of pharmacological therapy options in dementia is necessary.