# Mechanisms of X-Chromosome-dependent Sex Difference inAlzheimers Disease

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $2,267,022

## Abstract

PROJECT SUMMARY/ABSTRACT
Biologic sex influences Alzheimer's disease (AD) and whether sex chromosomes play a role is unknown. This
grant focuses on X-chromosome-derived mechanisms of sex difference that contribute to AD by integrating
mouse model and human studies. Understanding this largely unstudied area may reveal new X-based pathways
that could ultimately benefit both sexes. Sex differences in AD reveal differing vulnerabilities in men and women.
In brief, male sex is a risk factor for rapid progression to death in AD and other neurodegenerative conditions.
These findings support the fact that many more women have AD, due in part to their longevity and also to their
increased risk or incidence in older age – which together contributes to a higher lifetime risk of AD in women.
One major source of biologic difference between the sexes is that females have two X chromosomes and males
have one. Using genetic models of sex biology that dissect effects of gonadal development, sex chromosomes,
and X and Y chromosome dose, we found that the second X chromosome counters mortality, deficits and
toxicity related to hAPP/Aβ in both male and female mice and primary neurons, without altering levels of Aβ
or co-pathogenic proteins. Since one X inactivates in females, X dose is largely similar between the sexes. This
raises a key question: why would having two X's confer advantage to AD-related measures? While X
chromosome inactivation (XCI) silences one X chromosome in XX cells, a small subset of X-linked genes escape
XCI. Of these, Kdm6a (Utx), a H3K27-demethylase, robustly and consistently escapes in both mice and humans,
causes cognitive deficits in humans with loss of function mutations, and plays a post-developmental role in
synaptic plasticity and cognition. In further studies we identified that a second X chromosome confers
resilience to AD-related deficits, in part, through increasing Kdm6a. Furthermore, the X chromosome
escapee KDM6A may be relevant to human brain health since a genetic variant links to increased expression of
its gene product – and that variant assocaties with slower cognitive decline in a population of individuals
transitioning to AD. We hypothesize that the X chromosome escapee Kdm6a contributes sex difference and
confers resilience to AD and AD-related measures. Specifically, we will test how Kdm6a causes resilience – and
probe its molecular pathways. The complimentary clinical arm of this proposal enables us to examine key
associations of KDM6A in sex differences of human populations of aging and AD with existing cognitive and
biomarker data. Answers to our questions in mice and humans will fundamentally advance mechanistic
understanding of sex-based heterogeneity of AD, and will likely pave X-based paths toward urgently needed
treatments in AD, personalized for men, women, or both.

## Key facts

- **NIH application ID:** 10033567
- **Project number:** 1RF1AG068325-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Dena Bou Dubal
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,267,022
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033567

## Citation

> US National Institutes of Health, RePORTER application 10033567, Mechanisms of X-Chromosome-dependent Sex Difference inAlzheimers Disease (1RF1AG068325-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033567. Licensed CC0.

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