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

Grants and Contracts Details


This proposal is a response to RFA PAR-15-357: Understanding Alzheimer's Disease in the Context of the Aging Brain. Alzheimer’s disease involves accumulation of pathological levels of amyloid-beta (Aâ) and phospho-tau proteins, brain atrophy and a progressive loss of memory functions. However, a significant proportion of individuals with AD pathology and brain atrophy do not have clinical AD, indicating contributions of other factors. Increasing evidence suggests that neurocognitive patterns common in aging such—such as cerebrovascular alterations and related declines in executive function—contribute to clinical AD. This link is not straightforward though as the effects of AD pathology and white matter alterations can be moderated by cognitive reserve and brain resilience. Our recent results suggest that levels of Aâ and tau in cerebrospinal fluid (CSF) and cerebrovascular declines associated with white matter hyperintensity (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 Aâ, p-tau and t-tau, inflammatory markers, neuroimaging measures including event-related fMRI, and 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 be complete the same CSF and imaging measures approximately 3 years later. We aim to (1) understand the separate and synergistic effects of clinically silent pathology and cerebrovascular factors on neurocognitive functions, (2) determine the contributions of AD pathology and vascular measures to change in cognition over time and (3) identify reserve factors that moderate relationships between pathology, brain structure on functional imaging and cognitive patterns. We will test hypotheses that clinically silent 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. PUBLIC HEALTH RELEVANCE: Overall, this project will begin to dissociate the relative contributions of ‘normal’ aging and AD pathology to cognition in older adults and identify factors that may promote optimal cognitive aging.
Effective start/end date9/15/174/30/23


  • National Institute on Aging: $2,301,528.00


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