Rosenich Emily, Lim Yen Ying
Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, VIC, Australia.
Alzheimers Res Ther. 2025 Jul 18;17(1):165. doi: 10.1186/s13195-025-01776-w.
Beta-amyloid (Aβ) plaques and tau tangles are pathological hallmarks of Alzheimer's disease (AD); however, autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. It remains unclear how Aβ and tau relate to cognition in the context of concurrent CVD. In initially cognitively unimpaired older adults with CVD, this study aimed to determine ante-mortem cognitive trajectories associated with elevated Aβ and/or tau at autopsy.
Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer's Coordinating Center database, with ≥ 1 follow-up between 2005 and 2015, and available autopsy/APOE data were included in this cohort study (N = 863). All participants had at least one of six CVD markers at autopsy. Participants were classified into four groups (A - T-, A + T-, A - T+, A + T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging and Braak staging. Linear mixed models assessed rate of change in Preclinical Alzheimer's Cognitive Composite scores, episodic memory, and executive function.
A + T + adults demonstrated significantly faster cognitive decline on all outcomes in the ~ 10 years preceding death compared to A - T- adults (d = 0.34-0.46). Similarly, when compared to A + T - adults, A + T + adults showed significantly faster decline on all outcomes (d = 0.19-0.37). At the last visit prior to death, a greater proportion of A + T + adults (36%) received a dementia diagnosis compared to A - T+ (15%; OR = 6.00), A + T- (14%; OR = 8.00) and A - T- adults (12%; OR = 6.86), p <.001. When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p's < 0.001, d = 0.29-0.37) was similarly observed in A + T + adults compared to A - T- adults.
In older adults with concurrent CVD, A + T + at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A - T- older adults. Faster cognitive decline in A + T + in the context of low final visit dementia diagnoses may suggest that post-mortem A + T + is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.
β-淀粉样蛋白（Aβ）斑块和tau缠结是阿尔茨海默病（AD）的病理特征；然而，尸检研究表明，大多数老年人也存在脑血管疾病（CVD）标志物。目前尚不清楚在并发CVD的情况下，Aβ和tau与认知功能之间的关系。在最初认知未受损的患有CVD的老年人中，本研究旨在确定与尸检时Aβ和/或tau升高相关的生前认知轨迹。
本队列研究纳入了863名年龄在65 - 95岁之间、基线时被分类为认知未受损、2005年至2015年间有≥1次随访且有可用尸检/APOE数据的参与者，这些参与者来自国家阿尔茨海默病协调中心数据库。所有参与者在尸检时至少有六种CVD标志物中的一种。根据用于建立阿尔茨海默病神经炎性斑块分期和Braak分期登记处的半定量标准，将参与者分为四组（A - T -、A + T -、A - T +、A + T +）。线性混合模型评估临床前阿尔茨海默病认知综合评分、情景记忆和执行功能的变化率。
与A - T -成年人相比，A + T +成年人在死亡前约10年的所有结局指标上均表现出明显更快的认知衰退（d = 0.34 - 0.46）。同样，与A + T -成年人相比，A + T +成年人在所有结局指标上的衰退也明显更快（d = 0.19 - 0.37）。在死亡前的最后一次随访中，A + T +成年人中接受痴呆诊断的比例（36%）高于A - T +（15%；OR = 6.00）、A + T -（14%；OR = 8.00）和A - T -成年人（12%；OR = 6.86），p < .001。当分析仅限于排除痴呆诊断时，与A - T -成年人相比，A + T +成年人在所有结局指标上同样观察到明显更快的衰退（p值< 0.001，d = 0.29 - 0.37）。
在并发CVD的老年人中，与A - T -老年人相比，尸检时A + T +与死亡前10年更大的认知衰退相关。在最终随访时痴呆诊断率较低的情况下A + T +更快的认知衰退可能表明，死后A + T +与生前认知衰退的陡峭轨迹相关，但痴呆进展并非不可避免。
