Project Summary This is an application for an administrative supplement to enhance the outcome of the parent grant: U01 AG046139 “A Systems Approach to Targeting Innate Immunity in AD”. This Administrative Supplement aims to expand the multiomics profiling in this cohort and enable curation of exposome variables from existing brain bank records. The design of our unique study cohort in the parent award enables us to perform comparative analysis of control (no pathology), PathAg, (Pathologic Aging, amyloid+), AD (tau+, amyloid+) and PSP (progressive supranuclear palsy, tau+) providing a framework to identify therapeutic targets that play a role in the transition to different disease neuropathologic stages of AD. Further, comparisons between two brain regions (TCX=affected and CER=largely spared in AD) and between AD and PSP can help distinguish whether the molecular changes identified are likely a cause or consequence of pathology. We have collected multiomics measures in ~350 study participants, including genetic (WGS), transcriptomic (RNAseq) and epigenomic (ChIP- Seq) data. In collaboration with other consortia members, proteomic, metabolomic and lipidomic measures were/will also be collected. The study cohort in the parent award is focused on non-Hispanic White (NHW) individuals. Through the AMP-AD diversity initiative supplement, we expanded this study to understudied racial/ethnic minority cohorts comprising African American (AA) and Latin American (LA) participants. These efforts have generated complementary genetic, transcriptomic and proteomic measures on >200 diverse individuals. However, complementary DNA methylation data is currently lacking from both the parent (NHW) and the diversity supplement (AA, LA) cohorts. The samples in both cohorts are from the Mayo Clinic brain bank and have undergone in-depth neuropathological examination. A similarly in-depth review of available records to curate data on demographic, lifestyle (education, smoking and alcohol consumption), comorbid diseases, as well as specific neuropathological findings indicative of cerebrovascular disease is currently lacking. We hypothesize that the exposome interacts with the epigenome to drive gene expression changes which may underlie regional, cellular and ethno-racial vulnerabilities to neuropathology and ultimately neurodegenerative disease. The goal of this Supplement is to extract and collect exposome and DNA methylation data respectively for participants in the Mayo Clinic AMP-AD cohorts. Our specific aims are: 1. Identify exposome variables in an established post-mortem cohort of multi-ethnic participants with existing and new (methylome) brain multi-omics data. 2. Discover differentially methylated regions in brain associated with AD/ADRD diagnosis, neuropathology, and exposome phenotypes. 3. Identify impacts of AD, related neuropathologies and exposome phenotypes on the DNA methylation profile of key brain cell types in AD. We expect to identify differential...