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bioRxiv · 10.1101/2025.05.15.654279

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.
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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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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. Sex-Specific Differential DNA Methylation in Mild Cognitive Impairment and Alzheimers Disease. https://doi.org/10.1101/2025.05.15.654279

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