# Dissect the interplay between sex and APOE at the single cell level to uncover novel pathways, targets and therapeutics for Alzheimer's disease

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $3,641,905

## Abstract

Project Summary
Alzheimer’s disease (AD) is a multifactorial disorder with complex etiologies and the impact of sex on AD varies
over the course of clinical and neuropathological development. Basic and clinical research studies support sex-
specific contributions to AD pathogenesis and progression. Apolipoprotein E4 (APOE4) allele has been identified
as a primary genetic risk factor. The interplay between sex and APOE4 allele in AD risks, clinical manifestation,
pathological processes as well as treatment responsiveness in various clinical trials have been explored.
However, the molecular mechanisms underlying sex dimorphism in AD and how APOE4 stratifies sex divergence
in AD remain elusive. Multi-omics data in tandem with systems biology approaches offer a new avenue to not
only dissect sex- and APOE-stratified molecular mechanisms of AD but also develop sex-specific diagnostic and
therapeutic interventions for AD. Single-cell transcriptomic datasets as well as cell deconvolution of bulk tissue
transcriptomes provide in-depth insights into brain region-specific and cell-type specific impact on sex
dimorphism in AD. In this application, we propose to develop sex- and APOE-specific network models of AD by
performing integrative multiscale network analysis of large-scale bulk and single multi-omics data. In particular,
we will develop the first cohort of single nucleus multi-omics data in AD (simultaneous RNA-sequencing and
ATAC-sequencing of each single cell) that can meaningfully be stratified by sex and APOE genotype. We will
also curate existing single nucleus RNA-seq datasets in AD and combine with our own single cell multi-omics
dataset to identify sex-specific genetic variants and molecular signatures of AD (Aim 1). We will perform
integrative network analysis to investigate the interplay between sex and APOE genotypes in AD at brain-region
and single-cell levels and identify from the network models sex- and APOE-specific, network drivers for AD (Aim
2). We will then identify potential therapeutics of selected key drivers with drug candidate prediction through
virtual clinical trials of large electronic medical record (EMR) databases (Aim 3). Finally, we will functionally
validate the top predicted sex- and APOE-specific molecular network drivers by genetic manipulations (up- or
down-regulation of gene expression), as well as pharmacological perturbation with drug candidates identified
from virtual drug screening using relevant human iPSC culture systems and AD mouse models (Aim 4). The
findings from this project will guide future development of efficacious sex- and APOE-stratified interventions for
AD.

## Key facts

- **NIH application ID:** 10300781
- **Project number:** 1RF1AG074010-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dongming Cai
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $3,641,905
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10300781

## Citation

> US National Institutes of Health, RePORTER application 10300781, Dissect the interplay between sex and APOE at the single cell level to uncover novel pathways, targets and therapeutics for Alzheimer's disease (1RF1AG074010-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10300781. Licensed CC0.

---

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