PROJECT SUMMARY/ABSTRACT Mexican older adults are projected to face disproportionate rates of Alzheimer's disease and related dementias (ADRD) [1], but the underlying environmental and genetic factors accounting for these ADRD disparities are not fully understood. A proposed mechanism for these disparities is the cumulative disadvantage theory, wherein differential exposure to different genetic or environmental risk factors across the life course accumulate in ways that contribute to greater prevalence of ADRD [2-4]. However, the ability to systematically test whether this theory accounts for the observed disparities has been hindered by a lack of research on genetic and social environmental ADRD risk factors among Mexican older adults. The proposed study will clarify environmental conditions under which genetic expression of ADRD in Mexican older adults is maximized and minimized. First, I will specify effects of multiple environmental factors (i.e., education, literacy, socioeconomic status, rurality, and migration) on ADRD risk. Second, I will test the modifying role of each environmental factor on effects of apolipoprotein-E (APOE) on ADRD risk. Third, I will test the modifying role of each environmental factor on effects a polygenic risk score (PRS) for ADRD developed specifically in persons of Mexican ancestry on ADRD risk. No research to date has examined gene-by-environmental risk factors for ADRD risk in Mexican older adults. The proposed study will leverage a large-scale community-based dataset, the Mexican Health and Aging Study (MHAS; Mexico), the sample in which the Mexican origin PRS has been developed. The proposed training and research plan address the following research questions: Which environmental risk factors contribute to ADRD risk in Mexican older adults? To what extent do environmental risk factors moderate effects of common ADRD genetic risk variants in Mexican older adults? To address these questions, the following specific aims will be addressed: 1) Test whether the environmental factors influence ADRD risk scores in Mexican older adults via a latent dementia index (LDI); 2) Test whether environmental factors moderate APOE ε4 effects on LDI scores in Mexican adults; 3) Test whether environmental factors moderate the Mexican origin PRS effects on LDI scores in Mexican older adults. The proposed project will be the first study to elucidate the genetic and environmental influences that may underlie the elevated ADRD risk in Mexican older adults. Improved understanding of the role of these factors will also have important implications for public health, as this study will provide empirical evidence to inform and develop targeted intervention strategies that may mitigate ADRD risk among Mexican older adults.