Elucidating sex-specific risk for Alzheimer's disease through state-of-the-art genetics and multi-omics

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ABSTRACT Alzheimer’s disease (AD) manifests itself differently across men and women, but the genetic and molecular factors that drive this remain largely elusive. AD is the most common cause of dementia, affecting over 5 million people in the USA alone, and till today remains essentially untreatable. Because AD has a strong genetic component, with inheritance estimates between 50-80%, studying the genetics of AD can importantly aid the discovery of novel drug targets. However, evidence from various lines of research suggests that sex differences are an integral part of AD. It is therefore crucial to study the genetics of AD in a sex-specific manner, as this will help the field gain important insights into disease pathophysiology, identify novel sex-specific risk factors relevant to personalized genetic medicine, and uncover potential new AD drug targets that may benefit both sexes. To date, surprisingly few sex-specific variants/genes have been identified, which we hypothesize is because prior studies were faced with several obstacles such as data limitations and unexplored research avenues. This project proposes to use big data together with state-of-the-art approaches in order to leverage established sex differences in AD as a means of elucidating novel AD risk genes. Aim 1 will improve on prior sex-stratified genome-wide association studies (GWAS) by using larger sample sizes and extensively harmonized data. This includes a cross-cohort phenotype harmonization and powerful models using age information to improve AD risk associations. In addition, we will, for the first time, explore the role of rare variants on AD in a sex-specific manner. Aim 2 will use parallel strategies to Aim 1, but will focus on the X chromosome, which has remained largely unexplored in the field of AD genetics. For both Aims 1 and 2, we will further validate putative associations by evaluating their sex-specific effects on gene transcript expression and protein levels in brain tissue. Similarly, associations will be validated in a sex-specific manner using AD-relevant endophenotypes (e.g. tau levels in the cerebrospinal fluid) from deeply phenotyped cohorts. Aim 3 will follow a different innovative approach to sex- specific AD gene discovery by identifying sex-specific AD-related protein changes in brain tissue and determining the genetic variants that drive them. The latter variants will then be validated by relating them to risk for AD. The independent phase of this project will focus on the use of multi-omics data to corroborate sex-specific gene associations with AD risk, as well as proteomics data to discover new AD risk genes. Central to the success of this proposal, Dr. Belloy will have the support from an established group of experts in genetics, imaging, and neurology (Dr. Michael Greicius), multi-omics data integration (Dr. Stephen Montgomery), proteomics analyses (Dr. Nicholas Seyfried), sexual dimorphism (Dr. Marcia Stefanick), and rare variant analyses (Dr. Zihuai He), providing him with the necessary skillsets to embark on a career as an independent scientist.