Associations of Epigenetic Age Acceleration with Motor Impairment: Evidence from the PPMI Cohort

ObjectiveMotor decline is a hallmark of Parkinsons disease (PD) and biological aging. While epigenetic clocks measure systemic biological aging, their specific relationship with neuromotor function in the context of aging and neurodegeneration remains under-characterized. This study utilized data from the Parkinsons Progression Markers Initiative (PPMI) to examine the relationships between multiple DNA methylation-based epigenetic aging measures and motor impairment across distinct domains. MethodsWe utilized longitudinal phenotype and whole-blood DNA methylation data from the PPMI cohort. Seven epigenetic aging measures were calculated, including first-generation clocks (Horvath v1, Hannum), risk-optimized second-generation clocks (PhenoAge, GrimAge v1 and v2), a deep-learning estimator (AltumAge), and a pace-of-aging biomarker (DunedinPACE). Motor function was assessed using the MDS-UPDRS, which captures patient-reported disability, global staging (Hoehn & Yahr), and specific motor signs, including tremor, bradykinesia, and postural instability. Cross-sectional associations were evaluated using binary or ordinal logistic regression, while longitudinal repeated measures were analyzed using generalized estimating equations (GEE) and cumulative link mixed models (CLMM), with adjustments for multiple comparisons made using the false discovery rate (FDR). ResultsCross-sectional analyses yielded limited evidence, identifying only a specific association between Horvath v1 acceleration and postural tremor in males (PFDR < 0.1). Repeated-measures analyses in the overall sample revealed robust associations between accelerated epigenetic aging and worsening tremor phenotypes (postural and kinetic), while associations with gait, rigidity, and bradykinesia were largely non-significant or inversely related. Sex-stratified analyses revealed distinct sexual dimorphism: males exhibited a broad, multi-clock phenotype (involving Horvath v1, PhenoAge, and GrimAge), where accelerated aging was associated with worsening tremor, gait, and rigidity. Females showed restricted associations, primarily linking the Hannum clock to tremor and global staging, and DunedinPACE to rigidity. ConclusionsAccelerated epigenetic aging is robustly associated with the longitudinal progression of tremor impairment in PD, with associations being particularly consistent and multi-dimensional in men. These findings suggest that systemic biological aging, as captured by both first- and second-generation clocks, disproportionately exacerbates tremor circuitry distinct from the dopaminergic pathways that drive bradykinesia. Epigenetic clocks may serve as valuable biomarkers for monitoring progression and risk stratification, particularly for tremor-dominant phenotypes.