Epigenetic age acceleration and prevalent age- related neurological disorders: a two-sample Mendelian randomization study

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Abstract Age-related neurological disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and stroke, pose an increasing global health burden. Epigenetic age acceleration (EAA), measured through DNA methylation-based epigenetic clocks, has emerged as a promising biomarker that links biological aging to disease susceptibility. This study employs a two-sample Mendelian randomization (MR) approach to investigate the causal impact of EAA on neurological outcomes, utilizing genetic instruments derived from large-scale genome-wide association studies (GWAS) for epigenetic clocks, including HannumAge, GrimAge, and plasminogen activator inhibitor-1 (PAI-1). MR analyses identified significant associations between specific epigenetic clocks and neurological diseases. HannumAge was positively associated with an increased risk of multiple sclerosis (OR = 1.068, 95% CI 1.005–1.173, p = 0.047), while elevated PAI-1 levels were linked to a higher risk of Alzheimer’s disease (OR = 1.00008, 95% CI 1.000006–1.000163, p = 0.035) and a reduced risk of stroke (OR = 0.999998, 95% CI 0.999997–1.0, p = 0.024). Additionally, GrimAge was inversely associated with Parkinson’s disease risk (OR = 0.903, 95% CI 0.819–0.995, p = 0.04). These findings provide evidence for a potential causal relationship between EAA and neurological disorders, highlighting the utility of epigenetic clocks in elucidating aging mechanisms and informing diagnostic, prognostic, and therapeutic strategies. Further research is warranted to assess the clinical implications of EAA in personalized medicine and neurodegenerative disease prevention.

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