# Multimodal single-cell genomic and epigenomic analyses elucidate Alzheimer’s sexual dimorphism in human immune systems aging

> **NIH NIH R56** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $1,205,802

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is sexually dimorphic in its prevalence, incidence, symptomology, and neuropathology,
but the mechanisms underlying these sex differences are not well understood. While sex differences in
susceptibility to inflammation and AD progression have been reported, the relationship between local and
systemic inflammation and sex differences remains to be determined. Our preliminary single-cell genomic
analyses have identified sex-specific microglial gene signatures in AD patient brains. Bioinformatics analyses of
single-cell transcriptomic data of human peripheral blood mononuclear cells (PBMCs) imply that multiple sex-
specific, candidate pro-inflammatory genes are highly expressed in myeloid-derived suppressor cells (MDSCs)
in AD. We therefore posit that an interplay between microglia and systematic inflammatory mechanisms (termed
the “peripheral-central neuro-immune interactome”) exists and that understanding this system will be
essential to improve the mechanistic elucidation of AD pathogenesis in a sex-specific manner. Recent advances
of multimodal single-cell genomic and epigenomic analyses have shown the potential to provide a
comprehensive understanding of the neuro-immune and peripheral immune systems underlying sex
differences in AD. Integration of the single-cell transcriptome, epigenome, the human interactome, along with
large-scale genetic loci from genome-wide association studies are essential for such identification. To address
this hypothesis, our short-term goal is to identify next-generation immune modulators for AD sex differences
and molecularly targeted treatments for male and female patients with AD. We will leverage large-scale single-
cell genomic and epigenomic data generated from human brains and bloods with varying degrees of AD
pathology available at our two National Institute of Aging (NIA)-funded Alzheimer's Disease Research Center
(ADRCs) at the Cleveland Clinic and University of Washington. Aim 1 will test the hypothesis that central neuro-
immune transcriptional networks mediate sex differences in AD using single-nucleus genomic and epigenomic
analyses of human brains. Aim 2 will test the hypothesis that cell type-specific central neuro-immune and
peripheral immune interactome network changes in AD pathogenesis act in a sex-specific manner. In parallel,
we will utilize network-based, single-cell multi-omics analyses in AD transgenic mouse models to identify immune
cell type-specific promoters and enhancers that encode sex-specific master gene regulatory networks for AD.
Aim 3 will test the hypothesis that sex-specific, peripheral-central neuro-immune interactome networks in AD
can be targeted via pharmacologic treatment to reduce AD progression. We will use our well-established network
proximity methodologies to identify sex-specific repurposable drugs that influence the immune response using
mouse models and validate preclinical findings in large patient databases using state-of-t...

## Key facts

- **NIH application ID:** 10467465
- **Project number:** 1R56AG074001-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Lynn Bekris
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,205,802
- **Award type:** 1
- **Project period:** 2021-09-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467465

## Citation

> US National Institutes of Health, RePORTER application 10467465, Multimodal single-cell genomic and epigenomic analyses elucidate Alzheimer’s sexual dimorphism in human immune systems aging (1R56AG074001-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10467465. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*