# Investigating Genomic Instability and Loss of the Y Chromosome in Alzheimer’s Disease

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $422,125

## Abstract

PROJECT SUMMARY
Since the early 90's, genetic factors have been shown to play a formidable role in contributing to Alzheimer's
Disease (AD) risk. More recently, mosaic loss of the Y chromosome (LOY) has emerged as a novel risk
biomarker for AD, and was confirmed by our own study to confer between a 1.63 to 2 fold increased hazard for
AD diagnosis. LOY is a somatic event that occurs in males as they age. While the underlying biological
mechanism that drives this risk remains unknown, genome wide association studies (GWAS) of LOY outcomes
identified ~156 loci that contain genes involved in cell cycle regulation, mitotic pathways, and DNA damage
response. The discovered genomic variants also predict X chromosome loss in women, suggesting that LOY is
a marker of genomic instability in males that precedes the AD clinical phenotype. Typical AD pathology
includes the abnormal production and accumulation of amyloid beta and tau proteins, which ultimately leads to
plaques and neurofibrilary tangles, neuronal death, and loss of brain cortical volume. Bolstered by both genetic
and molecular studies, the clearance of abnormal proteins by microglia has emerged as an important disease
mechanism; immune system function is now thought to play a critical role in AD. In this project, we will
investigate the relationship between LOY and AD pathogenesis. We hypothesize that in the context of
Alzheimer's Disease, LOY in males is a marker of acquired genomic instability increasing risk of AD through a
neuronal or glial senescence phenotype. We will examine this hypothesis through a unique fusion of
population-level analyses and molecular experiments to 1) examine whole-blood transcriptomic changes in
LOY+ individuals; and 2) determine differences in immune cellular function using induced pluripotent stem cell
lines (iPSCs) with LOY.

## Key facts

- **NIH application ID:** 10740136
- **Project number:** 1R21AG079196-01A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** HOLLY N CUKIER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $422,125
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740136

## Citation

> US National Institutes of Health, RePORTER application 10740136, Investigating Genomic Instability and Loss of the Y Chromosome in Alzheimer’s Disease (1R21AG079196-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10740136. Licensed CC0.

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