SUMMARY Alzheimer’s disease (AD) is heritable with a large proportion of phenotypic variability explained by genetic components. Identifying these factors, particularly those that are modifiable in plasma biomarkers, could lead to effective AD treatments and risk reduction strategies. Multi-ethnic studies showed that population differences in genetic background can be leveraged to make novel discoveries that might require a sample sizes several orders of magnitude larger than existing subject collections to achieve similar success within a single sub- population. Genome-wide association study (GWAS) for AD has been focused on mostly Europeans ancestry, especially lacking a large-scale GWAS in Asian Americans and Canadians. Heritability of AD is currently unknown in Asians, and AD polygenic risk score applicable to Asians has not been established. The overarching goal of the Project 1 is to uncover risk and protective variants for AD and plasma biomarkers in the Asian Cohort for AD (ACAD). We propose a comprehensive approach in three specific aims. For Aim 1, we will identify risk and protective variants for AD in ACAD participants and compare the results to Asian and non-Asian populations. In collaboration with Data Management and Analysis Core (Core D), this is the first major AD genetics study of Asians in the US and Canada and will compare results with existing East Asians and multi-ethnic datasets obtained from the Alzheimer Disease Genetic Consortium (ADGC). For Aim 2, we will understand genetic architecture for plasma AD biomarkers in ACAD participants. We will identify quantitative trait loci (QTL) for plasma AD related biomarkers including Aβ peptides, total tau (t-tau), phosphorylated-tau (p-tau 181), and neurofilament light chain (NfL) in collaboration with Core D, Biosampe Core, and Project 2. For Aim 3, we will determine heritability of AD and establish AD polygenic risk score (ADPRS) in ACAD participants. Our study will provide insights on Asian ancestry specific (ASAC and/or Asians) and multi-ethnic targets in AD therapeutics. We anticipate that results from this study will facilitate potential novel, population-specific therapeutic targets for AD for treating and preventing AD. The results from this proposal will provide the important synergy to further investigate gene-environment interactions in Project 2.