Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Abstract

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Why Y matters? The implication of loss of Y chromosome in blood and cancer

“…9,13,36 Furthermore, investigations in large cohorts have revealed associations between hematopoietic mLOY and a broad spectrum of nonmalignant conditions, including Alzheimer's disease, diabetes mellitus, macular degeneration, and cardiovascular disease. [14][15][16][17][18][19][20][21][22][23] Consequently, there has been a research interest in hematopoietic mLOY and its association with age-related diseases.…”

“…Since 2014, studies have reported that hematopoietic mLOY leukocytes are associated with an increased risk of all‐cause mortality, particularly cancer‐related mortality 9,13,36 . Furthermore, investigations in large cohorts have revealed associations between hematopoietic mLOY and a broad spectrum of nonmalignant conditions, including Alzheimer's disease, diabetes mellitus, macular degeneration, and cardiovascular disease 14–23 . Consequently, there has been a research interest in hematopoietic mLOY and its association with age‐related diseases.…”

“…13 Furthermore, recent research has revealed an association between hematopoietic mLOY and an increased risk of various age-related diseases. These include Alzheimer's disease, [14][15][16] diabetes mellitus, 17 macular degeneration, [18][19][20] cardiovascular diseases, 17,[21][22][23] and nonhematological cancers. 24,25 More recently, it has been suggested that hematopoietic mLOY may causally contribute to the progression of heart failure by altering immune cell function, 23 indicating mLOY as a "causal" risk factor for age-related diseases.…”

Tau, ADNP, and sex

“…On the other hand, mosaic loss of chromosome Y (mLOY) is a common aging‐related somatic event associated with Alzheimer's disease. Using genome‐wide association studies to construct a mLOY polygenic risk score, associated a higher score with faster progression to Alzheimer's disease in men, with mild cognitive impairment (Garcia‐Gonzalez et al, 2023).…”

Genetic Analysis of 27 Y-STR Haplotypes in 11 Iranian Ethnic Groups

“…The pathophysiology of several diseases, including cancer, neuro-developmental, neuro-degenerative, and cardiovascular diseases (CVDs), is influenced by sex, affecting male development and metabolic homeostasis. [1][2][3] Numerous studies have reported how Y-chromosome haplotypes and haplogroups may help in understanding the etiology of complex diseases or manifestation of a medical outcome. [4][5][6] Recently published studies have shown that the Y-chromosome can play a role in CVDs and hypertension manifestation.…”