PROJECT SUMMARY – GENOMICS CORE The Mayo Clinic Alzheimer’s Disease Research Center (ADRC) and its related activities resulted in seminal contributions to the genomics of AD and related disorders (ADRD) since 1990. These include identification of AD genetic risk factors using endophenotype approach, discovery of familial mutations that cause frontotemporal lobar degeneration (FTLD) and/or amyotrophic lateral sclerosis (ALS), and genome-wide association studies (GWAS) of AD, Lewy body spectrum disorders (LBD) and FTLD/ALS. Mayo Clinic ADRC contributes to systems biology studies which integrate multi-omics and patient endophenotypes to discover novel therapeutic targets and biomarkers for ADRD and molecular underpinnings for vascular contributions to cognitive impairment and dementia (VCID). These studies are conducted under the NIH-NIA consortia, AMP-AD, M2OVE-AD, Resilience- AD, and CLEAR-AD in which Dr. Nilüfer Ertekin-Taner, the Director of the proposed ADRC Genomics Core, serves as PI. Mayo Clinic ADRC samples are widely shared internally or externally. These samples undergo characterizations including screening for disease/risk variants providing study inclusion criteria. These extensive core-type activities continued with piecemeal funding for >15 years, given lack of a Mayo Clinic ADRC Genomics Core. This proposal aims to establish a Genomics Core with the overarching objectives to a) centralize and standardize these activities to meet the needs of Mayo Clinic ADRC and external investigators and b) support innovative studies leveraging the rich collection of samples to discover genomic basis of the Multiple Etiology Dementias. We expect the proposed Genomics Core to successfully streamline the genomic sample management (Aim 1) and their multi-omics molecular characterizations (Aim 2); to determine the association between these multi-omics measures and the exposome (Aim 3) and to share these outcomes broadly (Aim 4). Our diverse Core Leadership and all aims are aligned with the PEDP. Our aims are to: Manage samples for genomic analysis: We will standardize and centralize the DNA/RNA extraction, QC, internal/external distribution and data management of the samples. Perform systematic multi-omics molecular profiling of Mayo Clinic ADRC samples: We will perform genomic characterizations of samples from all ADRC participants including AD, FTLD and LBD spectrum diagnoses using both existing (GWAS/WGS) and new molecular data (RNA/methylation). Determine the association of exposome and multi-omics measures: Exposome including but not limited to structural and social determinants of health (SSDoH) will be curated and included in innovative analyses. Share data, algorithms, and summary outcomes with the ADRC and the research community: This will be accomplished by collaborations with the NACC and NIA-approved data repository AD-Knowledge Portal. In summary, the proposed ADRC Genomics Core will oversee the essential functions of genomics sample manage...