Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

Original publication

DOI

10.1016/j.ajhg.2016.05.014

Type

Journal article

Journal

American journal of human genetics

Publication Date

06/2016

Volume

98

Pages

1208 - 1219

Addresses

Department of Immunology, Genetics, and Pathology, Uppsala University, 75108 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, 75123 Uppsala, Sweden. Electronic address: jan.dumanski@igp.uu.se.

Keywords

European Alzheimer’s Disease Initiative Investigators, Chromosomes, Human, Y, Humans, Alzheimer Disease, Prognosis, Risk Factors, Case-Control Studies, Longitudinal Studies, Prospective Studies, Mosaicism, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male