Associations of Epigenetic Age Acceleration with Motor Impairment: Evidence from the PPMI Cohort
Bibliographic record
Abstract
Objective: Motor decline is a hallmark of Parkinson's 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 Parkinson's Progression Markers Initiative (PPMI) to examine the relationships between multiple DNA methylation-based epigenetic aging measures and motor impairment across distinct domains. Methods: We 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). Results: < 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. Conclusions: Accelerated 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".