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 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.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that leads to a progressive decay of cognitive abilities and self-sufficiency
The selection criteria of publicly available DNA methylation (DNAm) datasets of healthy and AD human brains are described in Materials and Methods section, and the datasets included in the meta-analysis are reported in Tables 1, 2
In Frontal cortex (FC), sex-associated differentially methylated positions (sDMPs) were mainly hypermethylated in males compared to females (73% of hypermethylated probes) while the opposite was true for Temporal cortex (TC), Entorhinal cortex (ERC), and CRB (38, 33, and 36% of hypermethylated probes in TC, ERC, and CRB, respectively)
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that leads to a progressive decay of cognitive abilities and self-sufficiency. Neuronal loss involves multiple brain regions that are progressively affected by the disease. Hippocampus and entorhinal cortex exhibit the earliest pathological changes, preceding the onset of clinical signs and cognitive impairment by several years, and later the disease spreads to the other brain regions (Braak and Braak, 1991; Van Hoesen et al, 1991; Scahill et al, 2002; Coupé et al, 2019). More than 95% of cases of AD occur after 65 years of age (late onset AD), and AD prevalence increases exponentially between 65 and 85 years (Hebert et al, 1995; Kawas and Corrada, 2006). Two-thirds of clinically diagnosed cases of AD are women, and the fact that women live longer than man does not fully explain this sex bias for AD (Pike, 2017; Nebel et al, 2018)
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