Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease

Abstract Background Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock(definition) that could reflect biological aging. Objectives The aim was to evaluate whether PD age at onset is associated with DNAm‐age acceleration (difference between DNAm age and chronological age). Methods We used the genome‐wide Infinium MethylationEPIC array to assess DNAm age in discovery ( n = 96) and replication ( n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort ( n = 220) at four time points over a 3‐year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm‐age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36–75 years) and both idiopathic PD cohorts (26–77 and 35–81 years). Results DNAm‐age acceleration remained steady over the 3‐year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort ( P = 2.25 × 10 −15 ) and discovery idiopathic PD cohort ( P = 5.39 × 10 −9 ), suggesting that every 5‐year increase in DNAm‐age acceleration is related to about a 6‐year earlier onset. This link was replicated in an independent idiopathic PD cohort ( P = 1.91 × 10 −10 ). In each cohort, the faster‐aging group has an increased hazard for an earlier onset (up to 255%). Conclusions This study is the first to demonstrate that DNAm‐age acceleration is related to PD age at onset, which could be considered in disease‐modifying clinical trials. Future studies should evaluate the stability of DNAm‐age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society.