# Dissecting the role of sex-linked genes and APOE e4 risk in AD

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $1,190,459

## Abstract

Project Summary
Women have a higher lifetime risk of developing Alzheimer's disease (AD) than men. This increased risk is not
fully explained by differences in longevity, hormones or brain structure. Women who carry at least one copy of the
APOEɛ4 allele, the strongest genetic risk factor for late onset AD (LOAD), have accelerated neuropathology.
However, some studies suggest a faster decline in men, suggesting that sex bias may differ depending on the
stage of the disease. Here, we will investigate how the sex chromosome complement and sex-linked genes
influences sex differences in onset and progression of LOAD. Genome-wide association studies have identified
genetic and epigenetic risk factors for LOAD, but the sex-chromosomes are often excluded in these studies
meaning there is a lack of data on sex-linked genes. Males have unique Y-linked genes and females have higher
expression of genes that escape X inactivation. Interestingly, many of the escape genes are related to immune
function and neuroinflammation is a hallmark of AD, suggesting that these genes may directly contribute to disease
progression. To address the impact of sex-linked genes combined with APOEɛ4 alleles on neuroinflammation in
LOAD we will use unique cellular models and AD tissue for leveraging integrated omics and functional studies.
We will evaluate the functional roles of sex chromosomes and sex-linked genes in brain cell types using human
induced pluripotent stem cell (hiPSC) models. We have derived isogenic pairs of hiPSCs with a different number
of sex chromosomes on the same genetic background (XXY/XY or XXX/X). These new hiPSC lines minimize
variability between individuals, as well as environmental or hormonal confounders. We will generate isogenic pairs
of these lines with ɛ3/3 or ɛ3/4 alleles by gene editing. After differentiation of hiPSC into neurons, microglia, and
brain organoids we will employ a combination of `omic' analyses and functional assays focusing on
neuroinflammation and neurodegeneration. This approach will identify sex-linked candidate genes, which will be
tested for dosage effects by knockdown and overexpression. These in vitro studies will be validated in human
tissue collected by the Precision Neuropathology Core from our Alzheimer's Disease Research Center brain bank.
Using pathologically characterized AD brains we will employ myeloid-specific single-nucleus RNA sequencing to
determine the effects of sex and APOEɛ4 genotypes on microglial subtypes and neuroimmune gene expression.
Our new team combines expertise in hiPSC modeling, sex-linked genes, neuroinflammation, `omic analyses and
neuropathology. This integrative study will help understand sex-specific genetic factors and how those factors
interact with APOEɛ4 risk to modulate cellular dysfunction and pathology, thus providing novel insights into how to
tailor a more effective treatment for AD.

## Key facts

- **NIH application ID:** 10892895
- **Project number:** 5R01AG073918-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Christine M. Disteche
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,190,459
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892895

## Citation

> US National Institutes of Health, RePORTER application 10892895, Dissecting the role of sex-linked genes and APOE e4 risk in AD (5R01AG073918-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892895. Licensed CC0.

---

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