Psychological risk factors, quality of life, community, and brain aging in American Indians: The Strong Heart Study - PROJECT SUMMARY/ABSTRACT Every 65 seconds someone in the US is diagnosed with Alzheimer's Disease and Related Dementias (ADRD). American Indian (AI) adults have greater burden of cerebrovascular and ADRD-related comorbidities than their non-Hispanic white counterparts. AI adults also suffer disproportionate stress and trauma, and concomitant high rates of depression. Relatedly, AI adults also have high rates of substance misuse compared to other racial/ethnic groups. These public health problems become exacerbated as a population ages, since stress, depression and substance use have been linked to cognitive impairment later in life. Fortunately, improvements to health-related quality of life (HRQoL) and community connectedness may ameliorate these negative impacts, although none of these associations have been fully evaluated in AI adults. As impaired cognitive performance precedes development of ADRD, we will determine risk and protective factors of cognitive performance in AI adults to inform prevention strategies to potentially circumvent later development of ADRD. Longitudinal relationships between psychological risk factors and cognitive impairment need to be directly evaluated to examine the temporal sequence of clinical changes that occur with aging. Additionally, research testing the longitudinal relationship with cognitive performance and dementia in AI adults is missing. Established, longitudinal cohort studies offer opportunity to assess modifiable risk and protective factors in aging adults, with multiple data collections. Given these gaps in knowledge, our objectives are to test the longitudinal relationship among stress, depression, and substance use (alcohol, tobacco, prescription opioids) with cognitive performance in AI adults, and whether HRQoL and community connectedness moderate these relationships. Our central hypothesis is that higher stress results in higher depression, more substance use and especially misuse, and that all three are associated with lower cognitive scores, whereas better HRQoL and better community connectedness moderate these deleterious effects. Using the psychometrically-robust NIH Toolbox, we will also test and develop normative standards for the AI community, making it possible for the first time to directly compare AI cognitive data with non-Hispanic white, Asian, African-American, and Hispanic adults. Our proposed study is in partnership with the Strong Heart Study, a 30-year cohort of aging AI adults. We propose to collect these psychological and cognitive data in a follow-up examination (N=3,000). Defining associations among stress, depression, substance misuse, HRQoL, and community; and defining cognitive standards in a commonly used, established platform will inform future public health prevention and treatment strategies for this underserved, overburdened population.