NEURAL PHENOTYPES OF RESISTANCE AND RESILIENCY TO AD AND ADRD IN THE OLDEST OF THE OLD

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ABSTRACT FOR PROJECT 4 Prior work has described several factors that confer vulnerability for or protection against risk for the development of Alzheimer's disease (AD) and related disorders (ADRD), including demographic and social determinants of health, (e.g., socioeconomic status and education quality/skill), systemic and organ health (including conditions beginning at midlife, e.g. hypertension and obesity; examined in Project 1), lifestyle and wellness factors (e.g. physical activity and sleep quality; examined in Project 2), manifestations of menopause (e.g. vasomotor symptoms; examined in Project 3), as well as psychiatric (e.g. depression), and sociological (e.g. social network density) domains1. Some factors begin to influence risk for ADRD early in young adulthood and mid-life and promote cognitive impairment in relatively early old age. Thus, older adults vary greatly in function, with certain `unsuccessful' individuals exhibiting a reduction of cognitive abilities earlier in life. These individuals are in stark contrast to individuals in the latest decades of life who harbor cognitive risk factors but have successfully resisted pathology or exhibit resilience against cognitive impairment when pathology is present. Findings from the large autopsy cohort in the Rush Memory Aging Project demonstrated frequent discordance between cognition and pathology and noted the need to examine mechanisms of cognitive resilience2. Here, we aim to elucidate factors related to `successful aging' (minimal brain pathology and optimal cognition) in the latest stages of life. Studies have identified neural factors that contribute to relatively preserved functioning in the very-old3,4. In cohorts with AD pathology, high performing individuals have relatively larger hippocampal volumes than lower performing individuals5. This preservation in brain structure may confer cognitive resilience in certain individuals. We and others have found that vascular lesions modulate the level of AD pathology necessary for a given level of clinical impairment6,7 and that vascular lesion burden is associated with hippocampal atrophy8. It is therefore possible that superior vascular health (i.e., preserved vascular physiology and low vascular lesion burden) protects against impairment from early AD pathology. In the proposed work, we will examine the impact of advanced aging on structural and functional brain connectivity, neurochemistry, and cognitive abilities in groups stratified by cognitive performance (high/typical performance on a cognitive composite index), and cognitive risk (high/typical based on known risk factors; `allostatic load'). Aim 1. To determine patterns of brain connectivity and neurochemistry that confer superior cognitive performance in very-old (80+) adults. Aim 2. To determine associations among cerebrovascular health, connectivity, performance and lifespan risk and protective factors. Aim 3. To further define superior performance in the very-old based on patterns of `resistance' against the development of pathology (amyloid, tau, and neurodegeneration `A-T-N'; indexed via plasma amyloid β 42/40, p-tau, NfL, and hippocampal atrophy), or cognitive `resilience' in the face of existing pathologies. Successful completion of this work would uncover neural mechanisms associated with intact cognition in advanced aging.