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

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.

Grant Number: 5R00AG075238-05
NIH Institute/Center: NIH
Principal Investigator: Michael Belloy