Contributions of Alzheimer's Pathology and Cerebrovascular Factors to Cognitive Aging

阿尔茨海默病与病理标志物[淀粉样β蛋白]的积累有关 (aβ)和tau]，脑萎缩和记忆功能进行性丧失。然而，一个重要的 患有AD病理的人的比例没有发展为认知障碍，这表明 其他因素对临床AD的贡献。越来越多的证据表明， 与大脑老化有关，如脑血管改变和执行功能下降， 对临床阿尔茨海默病有贡献。然而，这种联系并不简单，因为AD病理的影响 认知储备和大脑韧性可以缓解血管变化。我们最近 结果提示脑脊液和脑血管中Aβ和tau的水平 与白质高信号(WMH)相关的下降与 认知正常老年人的执行功能模式。此外，我们的结果表明 其中一些模式似乎可以根据积极的生活方式变量进行修改。这项建议 旨在定义AD病理、脑血管相关改变和AD之间的相互作用 认知储备，区分正常的大脑老化和类似AD的认知衰退。我们 建议用脑脊液Aβ、p-tau和t-tau测定对12 0名认知正常的老年人进行研究 神经成像测量包括事件相关功能磁共振成像、多种结构成像测量。 结构性神经成像措施将包括体积测量、FLAIR成像 WMH体积的量化和弥散张量成像用于区域定量 弥漫性脑白质异常。一部分参与者将完成相同的CSF和 成像测量大约在3年后进行。我们的目标是(1)分离AD病理的影响 和脑老化对功能代偿的影响(2)确定单独和协同作用 AD病理和脑血管标记物对认知功能随时间的下降和(3)识别 调节血管和AD病理标志物之间关系的储备因子 认知力。我们将检验AD病理和脑血管因素协同作用的假说 相互作用，以预测类似AD的认知衰退。我们还将检验这一假设 这些因素将抵消其中一些病理和血管变化对认知的影响 功能，通过大脑维持或可塑性功能脑重组的机制 一些老年人的大规模脑功能网络。

Alzheimer's disease is associated with the accumulation of pathological markers [amyloid-beta (Aβ) and tau], brain atrophy and a progressive loss of memory functions. However, a significant proportion of individuals with AD pathology do not develop cognitive impairment, indicating contributions of other factors to clinical AD. Increasing evidence suggests that factors strongly linked with brain aging, such as cerebrovascular alterations and declines in executive function, contribute to clinical AD. This link is not straightforward though as the effects of AD pathology and vascular alterations can be moderated by cognitive reserve and brain resilience. Our recent results suggest that levels of Aβ and tau in cerebrospinal fluid (CSF) and cerebrovascular declines associated with white matter hyperintensities (WMHs) are differentially related to patterns of executive function in cognitively normal older adults. In addition, our results suggest that some of the patterns appear modifiable based on positive lifestyle variables. This proposal seeks to define the interplay between AD pathology, cerebrovascular-related alterations and cognitive reserve that distinguish normal brain aging from AD-like cognitive declines. We propose to study of 120 cognitively normal older adults using measures of CSF Aβ, p-tau and t- tau, neuroimaging measures including event-related fMRI, multiple structural imaging measures. Structural neuroimaging measures will include volumetric measures, FLAIR imaging for quantification of WMH volumes and diffusion tensor imaging for quantification of regionally distributed white matter abnormalities. A subset of participants will complete the same CSF and imaging measures approximately 3 years later. We aim to (1) dissociate effects of AD pathology and brain aging on functional compensation (2) identify the separate and synergistic effects of AD pathology and cerebrovascular markers on cognitive declines over time and (3) identify reserve factors that moderate relationships between vascular and AD pathology markers on cognition. We will test hypotheses that AD pathology and cerebrovascular factors synergistically interact to predict AD-like cognitive declines. We will also test the hypothesis that reserve factors will offset the effects of some of these pathological and vascular changes on cognitive functions, via mechanisms of brain maintenance or plastic functional brain reorganization of large-scale brain functional networks in some older adults.