The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study

Front Endocrinol (Lausanne). 2024 May 10:15:1372518. doi: 10.3389/fendo.2024.1372518. eCollection 2024.


Background: Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases.

Methods: Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results.

Results: The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk.

Conclusion: The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.

Keywords: Alzheimer’s disease; Mendelian randomization study; Multiple Sclerosis; Parkinson’s disease; epigenetic aging; neurodegenerative diseases.

MeSH terms

  • Aging* / genetics
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics
  • Epigenesis, Genetic*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Mendelian Randomization Analysis*
  • Neurodegenerative Diseases* / epidemiology
  • Neurodegenerative Diseases* / genetics
  • Parkinson Disease / epidemiology
  • Parkinson Disease / genetics
  • Plasminogen Activator Inhibitor 1 / genetics
  • Risk Factors


  • Plasminogen Activator Inhibitor 1

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Natural Science Foundation of China(No.82174486), San Ming Project Medicine in Shenzhen Nanshan(No. SZSM202103010), Scientific Research Project of Guangdong Provincial(No.20221135).