The present proposal seeks to characterize neural processes that affect cognition in normal aging distinct from early-stages of pathological change. Multiple brain changes are present in clinically normal aging including white-matter disruption, depletion of neurotransmitter systems, and preclinical Alzheimer's disease (AD) pathology. While it is common for all of these brain changes to be present in the same individuals, dissociations raise the possibility that certain components may reflect normal aging independent of the progression to clinical dementia. For example, we recently observed that white-matter integrity in normal aging was linked to executive dysfunction in the absence of amyloid deposition. Advanced aging is also associated with increased (often bilateral) recruitment of cortical systems, similar to that observed in other situations where brain systems are stressed. Activity increases are prominent in older adults who, as a group, display the brain changes noted above raising the possibility that they reflect a compensatory response. Testing hypotheses associated with cognitive aging is challenging because it is extremely difficult to identify a pure cohort of normal older adults that is sparred the preclinical stages of AD pathology. As a novel approach to the study of cognitive aging, we will explore the link between brain aging and executive dysfunction in a group of older adults screened for the presence of amyloid deposition using PET molecular markers. Specifically, we aim to (1) explore whether disruption of large-scale brain networks (via DTI and fcMRI) accounts for cognitive variation in the absence of amyloid deposition, (2) explore whether there is MTL-linked memory variance in normal aging that is independent of preclinical AD, and (3) explore whether activity increases are present in normal aging and mitigate cognitive decline. We hypothesize that there exists a prominent cascade affecting executive function during normal aging that is independent of amyloid plaque pathology and that activity increases are a response to mitigate the effects of this cascade. The cascade is proposed to arise from white-matter disruption and impaired coordination of large-scale brain systems. By completing this project, in addition to testing our specific hypotheses, we will generate and openly share a normative data set on aging that includes structural, functional, and cognitive data that is stratified by high or low amyloid deposition.
An increasing percentage of the population is living well beyond retirement age. Here we seek to understand the brain factors in normal aging that impair cognition as well as compensate to mitigate cognitive decline. By understanding these factors we hope to promote healthy, graceful aging.
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