Abstract
Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation differences in AD neuropathology, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort, we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with the AD Braak stage in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated genes in AD neuropathology, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation differences were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Our study implicated multiple new loci and biological processes that affected AD neuropathology in a sex-specific manner.
Highlights
Late-onset Alzheimer’s disease (LOAD) is the most common cause of dementia
Sex‐specific DNA methylation differences in AD neuropathology In the sex-stratified analysis, at 5% false discovery rate (FDR), our meta-analysis identified 381 and 76 CpGs, mapped to 245 and 51 genes in female and male samples, respectively (Fig. 1, Table 1, Additional file 2: Tables S3, S4)
Among all CpGs and all differentially methylated regions (DMRs), the effect estimates in males and females correlated only modestly, and about half (53% of CpGs, 54% of DMRs) were in the same direction of change in males and females, similar to what would be expected by chance
Summary
Late-onset Alzheimer’s disease (LOAD) is the most common cause of dementia. Women progress faster with more rapid cognitive and functional declines [3,4,5,6,7,8]. Previous studies have shown that epigenetics is an important contributor to the sex differences in brain functions and vulnerability to diseases [12,13,14,15,16]. DNA methylation profiles differ significantly between males and females at many loci in adult brains [17]. Alterations of DNA methylation levels have been implicated in multiple neurological disorders including AD [18,19,20,21,22]
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