PROJECT SUMMARY Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. A multitude of genetic studies in AD have identified multiple AD associated genes and loci, but a large portion of the genetic contribution to AD remains unknown. The Alzheimer Disease Sequencing Project (ADSP) is using large-scale sequencing efforts to increase our knowledge about the genetic variation that influences AD, particularly rare genetic variants that enhance AD risk or protect against AD. In the most recent wave of funding, the ADSP is sequencing individuals from the ADSP Follow-up Study (FUS) through AG057659 and AG062943. These efforts were specifically designed to improve racial and ethnic diversity in the ADSP datasets as well as to acquire unique and powerful data sets for gene discovery in NHW individuals, such as the Amish protective variant (AMISHPV) dataset, several large autopsy-confirmed series and the ADGC's early-onset AD dataset. The purpose of these studies has been to capitalize on differences in genetic backgrounds that may facilitate the identification of new protective and risk loci and ultimately address health disparities for AD and related disorders in underserved populations. Including the cohorts in this application, the ADSP-FUS will perform WGS on nearly 30,000 individuals. An added benefit of this application is the processing and delivery of high quality WGS and phenotype data on the new cohorts in this application. Specifically we propose to: (1) Increase the diversity and further enrich the clinical phenotype data of the ADSP through inclusion of ~1900 AD cases and controls from the Alzheimer Disease Center (ADC) Hispanic cohort, ~1500 AD cases and controls from the Faroe Islands, and ~3,200 AD cases and controls from the well characterized ethnically diverse A4 Clinical Trial Cohort; (2) work closely with the National Cell Repository for Alzheimer's Disease (NCRAD) in assembling DNA and blood on these existing cohorts which will ultimately serve as a central resource for the Alzheimer's disease research community; (3) generate genome-wide SNP array data and WGS data for all collected samples using established resources; (4) collaborate with NIAGADS, GCAD and the HIHG CGESG-PGNC QC Teams in processing, storage, and delivery of final datasets to NIAGADS for public data release; and (5) harmonize clinical data from newly acquired and existing FUS datasets to generate high quality inferentially equivalent phenotypes and endophenotypes. This project will merge several new cohorts into the ADSP-FUS to further enhance the ADSP as an invaluable resource for the Alzheimer's disease (AD) research community. These efforts will speed discoveries of targets for AD diagnosis, prevention, and treatment for all populations.