Somatic Loss of the Y Chromosome and Alzheimer’s Disease Risk

Abstract

Mosaic loss of the Y chromosome (LOY) is a somatic, age-related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer's Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis. In this study, we further validate the association between LOY and AD via prospective analyses of 1,447 males, and perform Mendelian Randomization analysis on 10,013 males across 26 US cohorts. Significant results from these analyses provide further evidence for a role of LOY in the development of Alzheimer's Disease.

Loss of Y is associated with multi-omic changes in immune cells from Alzheimer’s disease patients

“…The presence of one or two copies of APOE ε4 increased the risk to develop LOAD by a factor 3 up to 15-fold in a dose-dependent manner (Cacace et al 2016;Guo 2021). The replication of the association between LOY and AD in additional cohorts, also applying a different methodological approach, has recently been shown in two reports (García-González et al 2022;Palmer et al 2022). Other investigations of transcriptome further suggested that LOY might indeed be important in the pathogenesis of AD (Caceres et al 2020).…”