Basic Science and Pathogenesis.

Background: Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer's disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.

Method: The calling of mLOY was performed using the Mosaic Chromosomal Alterations (MoChA) pipeline, utilizing long-range phase information to search for imbalances between maternal and paternal allelic fraction in a cell population. A loss was called when the slope of coverage over allelic deviation was -0.94. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. The cognitively-impaired (CI) group combined AD, MCI and Unclear individuals and compared to the cognitively-unimpaired (CU) group. Individuals in 3 age groups (65-74, 75-84, ≥85) were included. To evaluate the association between mLOY and risk of developing CI in follow-up, we fit a Cox proportional hazards model associating mLOY to years of disease-free follow-up within individuals for whom blood was sampled prior to CI diagnosis.

Result: After extensive QC, 457 males (mean age = 80.48±5.12) were included. mLOY frequency increased with age (p = 0.029): 18.75% (65-74; n = 48), 31.86% (75-84; n = 317) and 39.13% (85+; n = 92). A subset of 372 males were assigned to the CU (n = 202) or CI (n = 170) group and mLOY was slightly higher in the CI group (26.2% in CU vs. 34.1% in CI; p = 0.099). Within 217 males for whom blood was sampled a priori, there were 48 subsequent CI events. mLOY was associated with an increased risk of CI diagnosis with hazard ratio (HR) = 1.90 (1.03-3.56, p = 0.04). After adjusting for the age of sampling, HR increased to 2.31 (1.23-4.36, p = 0.009).

Conclusion: We assessed the impact of mLOY in males on the risks of CI. We observed the same trend as reported in other European descent populations: mLOY increased with age and the higher sensitivity with WGS data compared with array-based data. We found that carriers of mLOY had an increased risk of impairment.