Malarte Mona-Lisa, Chiotis Konstantinos, Ioannou Konstantinos, Rodriguez-Vieitez Elena
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
J Neurochem. 2025 Sep;169(9):e70222. doi: 10.1111/jnc.70222.
Elucidating the earliest biological mechanisms underlying Alzheimer's disease (AD) is critical for advancing early detection strategies. While amyloid-β (Aβ) and tau pathologies have been central to preclinical AD research, the roles of peripheral biological processes in disease initiation remain underexplored. We investigated patterns of F-MK6240 tau positron emission tomography (PET) and peripheral inflammation across stages defined by Aβ burden and neuronal injury in n = 132 (64.5 ± 3.4 years old, 69.7% female, 10.7 ± 4.0 years of education, 34.1% APOE4 carriers) cognitively unimpaired late middle-aged Hispanic adults. F-MK6240 tau PET imaging revealed early entorhinal and neocortical tau deposition even in individuals lacking biomarker evidence of neuronal injury as measured by plasma neurofilament light (NfL). Peripheral inflammatory markers were not directly associated with Aβ or tau load but exhibited robust associations with neuronal injury (plasma NfL). Importantly, the hallmark biomarkers of AD proteinopathy (Aβ and tau) did not show a significant association with episodic memory performance, whereas peripheral inflammation and plasma NfL markers demonstrated links to subtle episodic memory impairment. Furthermore, Aβ and tau deposition appeared primarily influenced by genetic predisposition and sex, whereas peripheral inflammation was strongly associated with both neuronal injury (plasma NfL) and comorbidities including higher Body Mass Index (BMI) and Diabetes Mellitus (DM). These findings reveal a complex interplay between central and peripheral mechanisms in the potential earliest phases of AD pathophysiology and argue for the integration of peripheral inflammatory and neurodegeneration markers into models of preclinical AD progression. Recognizing the heterogeneity of early biological changes could refine risk stratification, biomarker development, and preventative strategies targeting inflammation and vascular health in cognitively unimpaired individuals at risk for AD.
阐明阿尔茨海默病（AD）潜在的最早生物学机制对于推进早期检测策略至关重要。虽然淀粉样蛋白β（Aβ）和tau病理一直是临床前AD研究的核心，但外周生物学过程在疾病起始中的作用仍未得到充分探索。我们在n = 132名（年龄64.5±3.4岁，女性占69.7%，受教育年限10.7±4.0年，APOE4携带者占34.1%）认知未受损的中老年西班牙裔成年人中，研究了F-MK6240 tau正电子发射断层扫描（PET）模式以及跨越由Aβ负担和神经元损伤定义阶段的外周炎症情况。F-MK6240 tau PET成像显示，即使在缺乏血浆神经丝轻链（NfL）测量的神经元损伤生物标志物证据的个体中，内嗅皮质和新皮质也存在早期tau沉积。外周炎症标志物与Aβ或tau负荷没有直接关联，但与神经元损伤（血浆NfL）表现出强烈关联。重要的是，AD蛋白病变的标志性生物标志物（Aβ和tau）与情景记忆表现没有显著关联，而外周炎症和血浆NfL标志物与轻微情景记忆损害存在联系。此外，Aβ和tau沉积似乎主要受遗传易感性和性别的影响，而外周炎症与神经元损伤（血浆NfL）以及包括较高体重指数（BMI）和糖尿病（DM）在内的合并症密切相关。这些发现揭示了AD病理生理学潜在最早阶段中枢和外周机制之间的复杂相互作用，并主张将外周炎症和神经退行性变标志物纳入临床前AD进展模型。认识到早期生物学变化的异质性可以优化风险分层、生物标志物开发以及针对有AD风险的认知未受损个体的炎症和血管健康的预防策略。
