The evidence for epigenetic age acceleration in neurological disease: A systematic review

BACKGROUND: DNA methylation-based epigenetic clocks estimate biological age. Epigenetic age acceleration (EAA), the difference between epigenetic and chronological age, reflects cumulative genetic, environmental, and disease-related influences. EAA has emerged as a potential biomarker of ageing and disease mechanisms. This systematic review synthesises evidence for EAA across neurological diseases. METHODS: This review followed PRISMA guidelines (PROSPERO: CRD42023464954). MEDLINE, Embase, Web of Science, and Scopus were searched from inception to October 2025. Eligible studies included adult human cohorts with neurological disease applying methylation-based epigenetic clocks and reporting clinical, neuroimaging, neuropathological, prognostic, or causal outcomes. Screening, data extraction, and risk-of-bias assessments were conducted independently in duplicate using Joanna Briggs Institute tools. Due to heterogeneity, findings were synthesised narratively. RESULTS: Seventy-nine studies were included across multiple neurological conditions. Fifteen clocks were applied, most commonly Horvath, Hannum, and PhenoAge. EAA was frequently altered in neurological disease, although associations varied by clock, tissue, and outcome. Central nervous system-derived measures showed more consistent relationships with neuropathological indices, whereas blood-based measures were more heterogeneous. Genetic and causal analyses provided limited and inconsistent evidence for direct causal effects. CONCLUSIONS: EAA captures biological ageing signatures relevant to neurological disease, but interpretation is context dependent. Current evidence does not support routine clinical use. Improved standardisation and validation may clarify the role of epigenetic ageing in neurological disease vulnerability.