ABSTRACT In 2020, ~5.8 million Americans suffered from Alzheimer’s disease (AD) of which ~5.6 million had late-onset AD (LOAD). One in 10 Americans age >65 has AD. Although >30 genes have been implicated in LOAD etiology, many more remain to be discovered. For many of these associations the causal variant has yet to be identified. Additionally, little is known how genes and genes and sex interact to increase susceptibility to LOAD. It has been shown that there is an association between AD and age-related hearing impairment (ARHI) and AD and tinnitus. However, it is unknown whether this association is driven by shared genetic risk factors (i.e. pleiotropy). Through the parent grant on ARHI and tinnitus we have developed a framework to study interactions and pleiotropy that can be applied to AD to bring about a better understanding of its etiology. As in the parent grant, the UK Biobank, one of the largest population-based studies available to the scientific community with extensive phenotype and genetic data on ~500,000 study subjects, will be analyzed. The findings will be replicated using an AD specific data set which contains 19,379 cases and 22,495 controls of African-American, Hispanic, and European ancestry who also have data on ARHI. For the UK Biobank, machine learning and data on >6,000 phenotypes, environmental exposures, cognitive measures, etc. will be used to generate AD probability scores, that will be used as a proxy for AD status. We will analyze these datasets for AD main effects and variant (v) x v, gene (g) x v, g x g, v x sex (s), and g x s interactions. For the replicated associations, fine-mapping will be performed using Bayesian credible set. For associations detected for ARHI and tinnitus in the parent grant, it will be determined if the same variants are associated with AD and ARHI and AD and tinnitus. For these variants, mediation analysis will be performed to determine if the observed pleiotropy is mediated or biological. This study should provide better insight into the genetic etiology of AD and the role of interaction in AD susceptibility as well an improved understanding of the relationship between AD, ARHI, and tinnitus.