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Sex-Specific Differential DNA Methylation in Mild Cognitive Impairment and Alzheimers Disease

Bergmann, P. E.; Madrid, A.; Papale, L. A.; Clark, L. R.; Asthana, S.; Johnson, S. C.; Keles, S.; Hogan, K.; Alisch, R. S.

2025-05-19 genomics
10.1101/2025.05.15.654279 bioRxiv
Show abstract

Sex differences in late-onset Alzheimers disease (AD) progression include accelerated decrements in cognitive status and greater amyloid and tau biomarker burdens in females. To identify sex-specific differentially methylated positions (DMPs) and genes in persons with mild cognitive impairment (MCI) and AD, we analyzed whole genome methylation sequencing on blood samples from participants with MCI (N=99, 52% female), AD (N=109, 43% female), and those cognitively unimpaired (CU; N=174, 52% female). Ninety-four percent of DMPs from MCI vs. CU, AD vs. CU, and AD vs. MCI pairwise comparisons were sex-specific. Female-specific DMPs were enriched in neurologic gene sets (e.g., synaptic membrane, ion channel complex), while male-specific DMPs showed limited enrichment. Sex-specific DMPs overlapped blood-specific enhancers, promoters, and transcription factor binding motifs, highlighting divergent epigenetic regulation by sex. These findings identify sex-specific genes and molecular pathways in MCI and AD and support that blood DNA methylation levels can distinguish cognitive status.

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