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

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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.