# Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $1,085,125

## Abstract

Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to dramatic effects on the
affected individuals and their families. While the characterization of the genetic contribution to AD and
underlying molecular mechanisms have advanced the understanding of the disease in recent years, studies
show that sex differences account for much of the observed differences in risk, progression, and severity
across individuals. Here, we directly dissect the contribution of sex-specific variation down to the region-
specific and cell-type-specific molecular basis by systematic profiling, computational integration, and
experimental validation of the transcriptional, epigenomic, and genetic signatures across individuals, brain
regions, and cell types. In Aim 1, we use genetic, epigenomic, and transcriptional profiles, generating millions
of single-cell (sc) level maps using scRNA-seq and scATAC-seq across human and mouse samples of varying
ages and genetic risk status. In Aim 2, we analyze the resulting datasets in the context of known AD genetic
risk variation and underlying molecular mechanisms, enabling us to discover and converge variants, regulatory
regions, genes, pathways, cell types, and brain regions to functional, causal mechanisms that drive sex-related
differences. In Aim 3, we use our well-established mouse and iPSC models to test our predicted mechanisms
with both high-throughput and cell-type specific assays. The resulting datasets, computational predictions, and
experimentally-supported mechanisms will shed light on the sex-related differences of AD and will help deepen
our understanding the disease in general as we develop more personalized therapeutic approaches in treating
AD.

## Key facts

- **NIH application ID:** 10495202
- **Project number:** 5R01AG074003-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Manolis Kellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,085,125
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495202

## Citation

> US National Institutes of Health, RePORTER application 10495202, Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s Disease (5R01AG074003-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10495202. Licensed CC0.

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