A workshop convened in 2013 by National Institute of Aging and the National Institute of Neurological Diseases and Stroke prioritized research on cognitive impairment of multiple etiologies, contributions of vascular brain injury (VBI) to neurodegeneration and Alzheimer’s Disease (AD), and disparities involving race, ethnicity, socioeconomics, and rural residence. VBI is a leading cause of accelerated brain aging and a major risk factor for stroke, cognitive decline, depression, and probable Alzheimer’s disease (AD). However, few studies have evaluated VBI, cognitive impairment, and AD in American Indians (AIs), who bear a heavy burden of risk factors for these conditions. This exclusion is unfortunate, since the distinctive history, risk profiles, environmental stressors, social environments, and healthcare systems of AIs likely result in patterns of disease that differ substantially from other populations. Our research team has conducted the only cohort study to date of covert VBI in AIs. In 2010-2013, Cerebrovascular Disease and its Consequences in American Indians study completed standardized clinical examinations, neuropsychological testing, and cranial MRI on more than 1,000 AIs aged 64-95 years from 10 tribes in 3 states. In 2016, we began re-examination of surviving participants using the same protocols, augmented by assessment for probable AD. However, the particular grant mechanism from the National Institute on Aging that provides funding for this follow-up examination is limited to data collection, with no resources allocated for analysis. In this proposal, we will capitalize on the accumulated longitudinal data to apply sophisticated imaging and analysis methods to quantify and evaluate associations for incident VBI, neurodegeneration, and changes in cognitive status in this elderly minority population. Our Specific Aims are to: (1) establish normative and diagnostic standards for mild cognitive impairment and dementia in elderly AIs, and evaluate associations and determinants for incident VBI, cerebral atrophy, cognitive decline, and probable AD; (2) conduct cluster analyses to identify novel neuroimaging profiles that predict subgroups of elderly AIs at highest risk for cerebral atrophy, cognitive decline, and probable AD; and (3) complete a rigorous career development plan that will position the applicant as an independent investigator and leader in innovative neuroepidemiology research with minority populations. This proposal leverages a timely opportunity to generate the first population-based estimates of and address novel scientific questions on VBI and cognitive impairment in AIs, a minority population with pervasive health disparities.