Project Summary/Abstract Up to half of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) cases are due to potentially modifiable exposures, including psychosocial factors. Exposure to traumatic events over the lifecourse is pervasive, particularly in groups that experience disproportionately high burden of AD/ADRD. Stress sensitization models suggest that trauma exposure, especially in early life, can result in brain changes and increase vulnerability to psychopathology. However, stress sensitization models have not been extended to late- life neurological outcomes and very little research exists on effects of lifecourse traumatic stress exposure on AD/ADRD risk. The scientific objective of this research plan is to understand effects of traumatic stress on cognition and neuroimaging in late life and to identify factors that modify these effects, including late-life contributors to resilience. Using state-of-the art statistical methods, the research will: (1) estimate the effect of traumatic stress over the lifecourse on late-life cognitive decline, dementia, and neuroimaging biomarkers of AD/ADRD, (2) identify individual characteristics and early-life factors (e.g. sex/gender, race/ethnicity, education) that modify the impact of lifecourse traumatic stress on late-life cognitive decline and dementia, (3) test the stress sensitization model to determine if childhood trauma and adversity modifies the effect of adulthood traumatic stress on late-life cognitive decline and dementia, and (4) identify late-life resilience factors (e.g. social support/integration, financial security, physical activity) that mitigate the impact of lifecourse traumatic stress on late-life cognitive decline and dementia. The proposed data work uses data from the US nationally-representative Health and Retirement Study (HRS) and pooled data from two newly available, harmonized, and diverse cohorts with robust neurocognitive assessments (Kaiser Healthy Aging and Diverse Life Experiences [KHANDLE] and Study of Healthy Aging in African Americans [STAR]). The research addresses the NIA strategic research directions related to understanding effects of personal, interpersonal, and societal factors on aging and disparities in aging. Understanding the impact of lifecourse traumatic stress, including effect modifiers and late- life resilience factors, will improve understanding of determinants of AD/ADRD and inform actionable strategies to prevent AD/ADRD and reduce AD/ADRD disparities. This research plan is complemented by a training plan that builds on the applicant’s background in epidemiology and biostatistics and includes new training to (1) gain strong foundational knowledge in the science and methods of brain and cognitive aging research; (2) develop expertise in the study of trauma and traumatic stress and their impact on brain health, and (3) gain skills in machine learning approaches for causal inference and identifying heterogeneous treatment effects...