UMMS Affiliation

Department of Neurology

Publication Date


Document Type



Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology


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 brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four 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. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex 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 varies 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 summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.


Alzheimer's disease, DNA methylation, aging, brain, sex

Rights and Permissions

Copyright © 2021 Pellegrini, Pirazzini, Sala, Sambati, Yusipov, Kalyakulina, Ravaioli, Kwiatkowska, Durso, Ivanchenko, Monti, Lodi, Franceschi, Cortelli, Garagnani and Bacalini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

DOI of Published Version



Pellegrini C, Pirazzini C, Sala C, Sambati L, Yusipov I, Kalyakulina A, Ravaioli F, Kwiatkowska KM, Durso DF, Ivanchenko M, Monti D, Lodi R, Franceschi C, Cortelli P, Garagnani P, Bacalini MG. A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration. Front Aging Neurosci. 2021 Mar 11;13:639428. doi: 10.3389/fnagi.2021.639428. PMID: 33790779; PMCID: PMC8006465. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in aging neuroscience


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

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.