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

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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.