PROJECT SUMMARY (ABSTRACT) Alzheimer’s disease (AD) and related dementias like frontotemporal dementia (FTD) disproportionately affect Latinos and socioeconomically disadvantaged groups. Nevertheless, the bulk of the research exploring the multifaceted biology of dementia, which includes both genetic and epigenetic aspects, has predominantly been focused on Caucasian populations and higher-income countries (HICs). To address these disparities and expand dementia research in Latin America countries (LAC) and low-income countries, our group has established the NIH-NIA/Tau Consortium/Alzheimer Association funded Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) cohort study of Latinos with AD, FTD, and healthy controls. ReDLat represents a first-in-class dataset of Latinos with AD, FTD, and demographically matched healthy controls consisting of biospecimen collection, standardized clinical, neuropsychological, genomic, neuroimaging, and SDH data, which our research group has utilized to identify unique combinations of environmental and genetic factors of dementia in Latin American Countries (LAC). Our preliminary epigenetic data reveals shared and distinct epigenetic DNA methylation differences related to AD and FTD, including a "Hispanic Paradox" with epigenetic biomarkers underestimating biological aging in Latinos despite AD and FTD diagnoses. Moreover, our preliminary data harnessing matched SDH data from ReDLat suggests a link between altered DNAm states of inflammatory, stress, and cardiometabolic genes and socioeconomic status. Our overall hypothesis is that a social adversity-epigenetic signature in immune cells at regulatory regions of proinflammatory, stress, and cardiometabolic genes associates with dementia presentation and heterogeneity in Latinos. In this proposal, we test this overall hypothesis and add epigenetic DNAm data to the ReDLat cohort by (1) leveraging existing blood biospecimens from 1,600 participants (n=400 AD, n=400 FTD, n=800 controls) with different social determinants of health (SDH) levels, including a low-middle income country (Colombia), an upper middle-income country (Argentina), and HICs countries (Chile and the US) and (2) leverage existing ongoing rolling ReDLat recruitment to add an out-of-sample validation epigenetic dataset of 400 additional participants (n=100 AD, n=100 FTD, and n=200 controls) to generate an epigenetic dataset from 2,000 total Latinos in ReDLat. With these rich epigenetic data, we will identify shared and distinguishing epigenetic DNAm features associated with AD and FTD presentation in Latinos. Moreover, we will utilize this extensive epigenetic dataset to better understand the interactions between specific SDH factors and distinct epigenetic changes in the genome. Understanding dementia presentation through the lens of epigenetics and SDH in Latinos across diverse regions of LAC and the US will advance regionally-informed novel strategies to address dementia ...