PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is a highly heritable complex human disease, but only a limited number of its genetic risk factors have been identified. In this project, we propose to leverage identical-by-descent (IBD) segments, which are expected to better tag haplotype effects and provide complementary genetic information to additively coded genotypes that are commonly used in genome-wide association studies, in the genetic association mapping for AD and related brain imaging endophenotypes. In Aim 1, we will develop the statistical and computational framework for efficient genetic association mapping using IBD segments in large samples. In Aim 2, we will apply IBD mapping to identify novel genomic regions associated with brain imaging endophenotypes from the UK Biobank. In Aim 3, we will replicate these associations in the Alzheimer’s Disease Sequencing Project (ADSP), develop and apply IBD mapping methods to AD, and combine association evidence from diverse populations in the UK Biobank and ADSP. Our novel tools and findings from this project will be made publicly available to facilitate novel discoveries that improve our understanding on the genetic architecture of AD and related brain imaging data.