https://jnnp.bmj.com/content/early/2025/12/30/jnnp-2025-336802.long
This does not surprise me as they are measuring DNA methylation in WBCs rather than in dopaminergic neurons.
Gemini:
Based on the article “Epigenetic ageing and the risk of Parkinson’s disease” published in the Journal of Neurology, Neurosurgery & Psychiatry (December 2025), here is the summary, identification of novelty, and critique.
Summary
This prospective nested case-control study investigated whether epigenetic age acceleration (EAA)—a measure of biological aging derived from DNA methylation—could predict the future risk of Parkinson’s disease (PD), its age of onset, or the time to phenoconversion (progression from prodromal to clinical disease).
- Methodology: The researchers analyzed blood samples from the Nurses’ Health Study cohort. Crucially, they utilized two sets of pre-diagnostic samples: one collected a median of 19 years before PD onset and another collected a median of 8 years before.
- Participants: The study included 75 individuals who developed PD, 79 with prodromal features, and 154 age-matched controls.
- Analysis: They applied six different epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge, DunedinPACE, and a cortical epigenetic clock) and adjusted for lifestyle factors such as smoking, physical activity, BMI, caffeine, and diet.
- Key Findings: The study found no consistent association between epigenetic age acceleration and the risk of developing PD at either time point. Furthermore, EAA did not predict an earlier age of onset or a faster time to phenoconversion.
- Conclusion: Epigenetic clocks measured in blood are not reliable biomarkers for predicting Parkinson’s disease risk or its onset, challenging the utility of these specific biological aging markers for PD prognosis.
Novelty
- Long-Term Prospective Design: The primary novelty lies in the extremely long follow-up period, analyzing blood samples collected nearly two decades before diagnosis. This is rare in PD biomarker research and effectively minimizes “reverse causation” (where the disease itself changes the biomarker).
- Negative Result Importance: The findings contradict the broader assumption that accelerated biological aging (as captured by current methylation clocks) is a universal driver or early warning sign for all neurodegenerative diseases. It distinguishes PD from conditions where EAA has shown stronger predictive value.
- Comprehensive Clock Comparison: Unlike older studies that might rely on a single metric, this study tested a broad suite of six distinct clocks, including “second-generation” clocks like GrimAge (predictive of mortality) and DunedinPACE (pace of aging), providing a robust stress-test of the hypothesis.
Critique
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Strengths:
- Rigorous Cohort: The use of the Nurses’ Health Study provides high-quality longitudinal data with extensive information on potential confounders (e.g., diet, smoking), ensuring that lifestyle factors didn’t skew the results.
- Temporal Depth: By checking samples at both ~19 and ~8 years pre-diagnosis, the study covers both the “pre-clinical” and “prodromal” phases, offering a complete picture of the disease timeline.
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Weaknesses & Limitations:
- Sample Size: With only 75 confirmed PD cases, the study is relatively small for a genomic/epigenetic analysis. It may lack the statistical power to detect very subtle effects or associations in specific subgroups.
- Tissue Specificity: The study relies on blood DNA, which may not perfectly reflect epigenetic changes occurring in the brain (substantia nigra). While the authors attempted to use a “cortical clock,” applying it to blood data is an imperfect proxy for neuro-specific aging.
- Demographics: The Nurses’ Health Study consists of female participants, and likely predominantly of European ancestry. This limits the generalizability of the findings to men (who have a higher PD risk) or other ethnic groups.
- Null Result Interpretation: While valuable, a null result (“no association found”) leaves open the possibility that other, yet-to-be-developed clocks could still be predictive, or that epigenetic changes occur only in specific cell types not captured by whole-blood analysis.
… DNA Methylation and Aging explanation …
This video is relevant because it explains the fundamental concept of epigenetic clocks (like the Horvath clock mentioned in the study) and how DNA methylation is used to measure biological aging, which is central to understanding the methodology critiqued above.