Epigenetic clock acceleration is linked to age-at-onset of idiopathic and LRRK2 Parkinson's disease

Parkinson's disease is a clinically and genetically heterogeneous movement disorder with highly variable age-at-onset. DNA methylation (DNAm) age is an epigenetic clock that could reflect biological aging. Studies of DNAm-age acceleration (difference between DNAm-age and chronological age) are pertinent to neurodegenerative diseases (e.g., Parkinson's disease), for which aging is the strongest risk-factor. We assessed DNAm-age in idiopathic Parkinson's disease (n=96) and a longitudinal LRRK2 cohort at four time-points over a 3-year period (n=220), including manifesting (n=91) and non-manifesting (n=129) G2019S-carriers. A highly variable age-at-onset was observed in both the idiopathic cohort (26-77 years) and manifesting G2019S-carriers (39-79 years). Increased DNAm-age acceleration was significantly associated with younger onset in idiopathic and LRRK2-related Parkinson's disease, suggesting that every 5-year increase in DNAm-age acceleration is linked to about 6-year earlier onset. At an individual level, DNAm-age acceleration remained steady over a 3-year period for most G2019S-carriers, indicating that it might serve as a stable biomarker of biological aging. Future studies should evaluate the stability of DNAm-age acceleration over longer time-periods, especially for phenoconverters from non-manifesting to manifesting subjects. In conclusion, DNAm-age acceleration is linked to disease onset, and could be used in disease-modifying clinical trials of prodromal Parkinson's disease.