# Sex-specific Molecular Profiling to Understand Pathology and Identify Causal Genes and Drug Targets for Alzheimer's Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $906,053

## Abstract

Abstract
Alzheimer's disease (AD) is a highly heterogeneous multifactorial disease. Genetic influences on AD are
strong as shown by several pathogenic genes and over 50 AD loci identified through genome-wide association
studies (GWAS). There are also clear sex differences in AD risk and progression. Women are at a higher risk
of developing AD and present faster progression. A recent GTEx study also highlights sex differences in the
genetic regulation of gene expression. Despite these established sex differences, sex-specific molecular
findings in AD are still limited. The objective of this study is therefore to generate detailed sex-specific multi-
tissue molecular profiles of AD and decipher the genetic architecture that underlies AD. We propose to identify
sex-specific functional mechanisms underlying the genetic architecture of AD. We will generate multiple layers
of -omics data, including DNA methylation, gene expression, proteomics, metabolomics, and lipidomics, from
several large and well characterized studies. A series of well-powered sex-specific omics characterization
across multiple tissues can help identify novel drug targets and provide critical insights for clinically translatable
interventions for prevention and treatment. We will then map additional GWAS loci by performing sex-specific
multi-omic quantitative trait loci and co-localization for each -omic layers. We will identify the causal genes,
proteins, and additional -omic analytes by performing Mendelian randomization. Analyzing such omics data will
elucidate a causal path from sex-specific genetic variation to AD risk, onset and progression. The human multi-
omic data will finally be combined with induced pluripotent stem cell (iPSC) models to identify novel sex-
specific FDA-approved therapeutics. We have assembled a very productive and interdisciplinary research
team with expertise in all the aspect of the proposal. All aims in this proposal will be conducted and reported in
compliance with NIH guidance on scientific rigor and reproducibility. Our preliminary data already identified
several genes and proteins that are associated with AD risk and cerebrospinal fluid biomarkers in a sex-
specific manner. All the raw data will be shared via NIA-approved mechanism (including AD Knowledge Portal,
NIAGADS). This rich resource will benefit the field for additional analyses beyond the ones proposed here.

## Key facts

- **NIH application ID:** 10891769
- **Project number:** 4R01AG074007-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** YunJu Sung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $906,053
- **Award type:** 4N
- **Project period:** 2021-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891769

## Citation

> US National Institutes of Health, RePORTER application 10891769, Sex-specific Molecular Profiling to Understand Pathology and Identify Causal Genes and Drug Targets for Alzheimer's Disease (4R01AG074007-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891769. Licensed CC0.

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