PROJECT ABSTRACT Alzheimer's disease and related dementias (ADRD) are known causes of cognitive and functional decline, but some individuals are more resilient to these diseases and continue to function normally despite associated brain changes. Cognitive reserve has been invoked to explain better cognition than expected based on the presence and severity of disease. There is evidence modifiable lifestyle factors may build cognitive reserve; elucidating these associations has major practical implications for public health policy and interventions to build reserve, thus reducing the impact of ADRD and promoting healthy aging. The overarching goal of this project is to transition from a hypothetical and often post-hoc construct of cognitive reserve to a concrete understanding of the variables that promote resilience and the mechanisms by which they protect against cognitive and functional decline. In this competitive renewal we will use novel imaging approaches, an unprecedented multi-racial/ethnic sample, and prospectively collected midlife data; each of these components constitutes a major innovation over previous studies. Aim 1 will delineate brain resources underlying cognition and everyday function. We will employ discovery-based neuroimaging techniques to better understand the contributions of cortical neurodegeneration, vascular brain injury, and amyloid deposition to cognitive and functional outcomes. We will leverage four longitudinal cohorts (N = >700) with harmonized imaging, cognitive and functional data among four major racial/ethnic groups (Latinos, non-Latino Asians, non-Latino Blacks, and non-Latino Whites) to examine racial/ethnic group similarities and differences in brain mechanisms underlying cognition and function. Models developed in Aim 1 will also serve to enhance the precision by which we can operationalize cognitive reserve as residual cognition after accounting for brain changes. We also extend our approach for cognitive reserve to operationalize functional reserve. Loss of independence is a major concern for older adults and better understanding factors that reduce disability is critical. Aim 2 will develop longitudinal models of cognitive and functional reserve and investigate how dynamic reserve impacts ADRD clinical outcomes. Aim 3 will evaluate how life course risk and resilience factors build or deplete cognitive and functional reserve and whether these relationships vary across racial/ethnic groups. A uniquely valuable contribution of this study will be the rare ability to examine impacts of medical, lifestyle, and psychosocial data (vascular risks, physical/cognitive activity, personality, stress/adversity and social connection) prospectively collected in the 1960s-1990s (during midlife) in addition to late life, thereby allowing us to answer important questions about critical periods of exposure for reserve and its life course determinants. This project will leverage unique data, multidisciplinary expertise, and ...