University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Neurology; Wellstone Center for FSHD

Publication Date

2020-12-02

Document Type

Article Preprint

Disciplines

Genetics and Genomics | Geriatrics | Nervous System | Nervous System Diseases | Neuroscience and Neurobiology | Psychiatry and Psychology

Abstract

Alzheimer’s disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in the brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of 4 brain regions (temporal, frontal, entorhinal cortex and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age- and AD-associated epigenetic profiles. We showed that DNAm differences between males and females tend to be shared between the 4 brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation changes also during aging is higher than expected, but that differences between males and females tend to be maintained, with only few probes showing sex-by-age interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm changes with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease.

In conclusion, we demonstrated that age-associated, but not sex-associated DNAm concurs to the epigenetic deregulation observed in AD, providing new insight on how advanced age enables neurodegeneration.

Keywords

Genetic and Genomic Medicine, Alzheimer’s disease, aging, sex, brain, epigenetic profiles, neurodegeneration, epigenetic modifications, DNA methylation

Rights and Permissions

The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

DOI of Published Version

10.1101/2020.11.25.20238360

Source

medRxiv 2020.11.25.20238360; doi: https://doi.org/10.1101/2020.11.25.20238360. Link to preprint on medRxiv.

Comments

This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

Full author list omitted for brevity. For the full list of authors, see article.

Journal/Book/Conference Title

medRxiv

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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