Genetic evidence suggests GrimAge may increase Alzheimer's disease risk, with no support for the reverse direction.
Evidence
A bidirectional study using GWAS summary data from 63,926 participants found GrimAge EAA associated with AD risk (OR 1.025, 95% CI 1.006-1.044, p=0.009).
Caveat
The positive signal was limited to one epigenetic clock, and Mendelian randomization depends on valid genetic instruments rather than direct intervention.
Simplified
BACKGROUND: Alzheimer's disease (AD) is identified by a distinct progression of aging-associated cognitive and functional impairment. Recent advances recognize the DNA methylation-based epigenetic clock as a precise predictor of aging processes and their related health outcomes. However, observational studies exploring this link are often compromised by confounding factors and reverse causality bias. To address the question, our study employs a bidirectional (MR) analysis to explore the causal relationship between (EAA) and AD.
METHODS: Genome-wide association study (GWAS) statistics for epigenetic clocks (GrimAge, PhenoAge, HorvathAge, and HannumAge) were sourced from Edinburgh DataShare and the Alzheimer Disease Genetics Consortium (ADGC). The dataset comprised 63,926 participants, and among them, 21,982 cases were AD patients and 41,944 were controls. The primary analytical method for the MR was the inverse variance weighted (IVW). The potential pleiotropy and heterogeneity among the instrumental variables were evaluated by additional sensitivity analyses.
RESULTS: Employing the random-effects IVW approach, we found that, as indicated by GrimAge, EAA was associated with an increased risk of AD (Odds Ratio [OR] = 1.025, 95% Confidence Interval [CI]: 1.006-1.044, p = 0.009). Quality control assessments confirmed the reliability and robustness of our findings. However, the evidence did not support a causal relationship between AD and epigenetic aging in the reverse direction.
CONCLUSIONS: Our MR study indicates a positive causal relationship between EAA and AD. Further research is necessary to explore the underlying physiological mechanisms.
Key numbers
1.025
Increase in AD risk
for measured by
63,926
Study population
Total participants in the study, including AD cases and controls
Full Text
We can’t show the full text here under this license.
