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Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
Open accessAbstract
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.
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“However, there is conflicting evidence regarding the impact of CH on Alzheimer’s disease (AD).5,10”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [10]
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“Mosaic chromosomal alterations, including loss of the Y chromosome (LOY), are strongly associated with cardiovascular disease, stroke, and dementia risk [34,44,45].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [45]
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Metadata
- Authors
- Dumanski, J. P., Lambert, J.-C., Rasi, C., Giedraitis, V., Davies, H., Grenier-Boley, B., Lindgren, C. M., Campion, D., Dufouil, C., Pasquier, F., Amouyel, P., Lannfelt, L., Ingelsson, M., Kilander, L., Lind, L., & Forsberg, L. A.
- Affiliations
- Uppsala University (SE)
- Inserm (FR)
- Broad Institute (US)
- Corresponding author
- Dumanski, Jan P.
- Forsberg, Lars A.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 98
- Issue
- 6
- Pages
- 1208-1219
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4908225
- OpenAlex
- W2403642712
- Cited by
- 266
- References
- 65
- Citations by year
- 2026: 35 · 2025: 42 · 2024: 33 · 2023: 33 · 2022: 22 · 2021: 33 · 2020: 19 · 2019: 22 · 2018: 14 · 2017: 10 · 2016: 3
- FWCI
- 14.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (WT098017, 086596, 086596/Z/08/Z, WT064890, WT090532)
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- Cancerfonden
- Hjärt-Lungfonden
- Vetenskapsrådet
- Akademiska Sjukhuset
- Uppsala Universitet
- Science for Life Laboratory
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- Y chromosome mosaicism, Alzheimer's disease, sex differences in mortality, blood cells, cancer risk, immune surveillance, smoking, all-cause mortality
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Longitudinal Studies, Male, Middle Aged, Mosaicism, Prognosis, Prospective Studies, Risk Factors, Case-Control Studies, Polymorphism, Single Nucleotide, Chromosomes, Human, Y
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