PROJECT SUMMARY African Americans have double the prevalence of Alzheimer’s disease (AD) as compared to white Americans. We do not sufficiently understand the causes of this health disparity. In particular, there continues to be a dearth of data on the cognitive and neural changes that occur across the lifespan in older African Americans and how these relate to health and lifestyle, environmental, and genetic risk factors for AD. During the current grant cycle, we have shown that low levels of aerobic fitness and poor sleep quality may be key drivers of cognitive decline and AD in older African Americans. However, the impact of these potentially-modifiable health and lifestyle variables are not uniform across all individuals: rather, genetic variations and socio- environmental factors interact in complex ways to moderate how aerobic fitness and sleep quality influence brain health. To investigate these knowledge gaps further, we will leverage our track record of sixteen years (2006-2022) of deep community engagement through innovative partnerships with churches, senior centers, medical clinics, public housing and other organizations that serve the greater Newark, NJ area that has contributed to our success in enrolling older African Americans. Specifically, we will recruit 240 cognitively healthy participants ages 60 and above, and retest them in years 3 and 4 for their Cycle II (two-year) follow up. All participants who are age 80 or above will be tested every year, due to higher likelihood of decline within one year. Participants who show preliminary signs of cognitive decline—but not sufficient to be classified as mild cognitive impairment (MCI) or AD—will also be tested annually. Despite the deaths of almost 10% of our cohort from Covid-19, we still project carrying forward 290 participants from our current R01 and previous R56 for Cycle III (four-year), Cycle IV (six-year) and/or Cycle V (8-year) assessments. Thus, modulo attrition, we project a net cohort of 530 people for this study representing a longitudinally-followed cohort of older African Americans. In addition to our prior cognitive, health, lifestyle, genetic, and MRI assessments, we now include an expanded focus on Social Determinants of Health (SDOH) as well as the addition of two blood-based biomarkers for AD neuropathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology, and phosphorylated tau, a marker of AD-related tau phosphorylation and secretion. Our existing community engagement and research infrastructure will enable the following four new Specific Aims: (1) Examine whether aerobic fitness and sleep quality interact with genetic variations to influence cognitive performance, neural function, and neuropathology in older African Americans; (2) Expand methodologies for studying SDOH by assessing the predictive value of a novel measure of neighborhood disadvantage that is based on spatial proximity to abandoned buildings; (3) Evaluate our novel...