Most Epigenetic Aging Clocks Fail to Predict Dementia, Meta-Analysis Finds

The work is a systematic review and meta-analysis posted on medRxiv as a preprint. A preprint has not been peer reviewed, so other experts have not yet checked it. The authors, led by Kua Z, combined 37 observational studies covering 46,365 people with seven Mendelian randomization studies. Observational studies can show links between two things. They cannot show that one causes the other.

These tests read DNA methylation, which are chemical tags on DNA that change with age. Different "clocks" turn those tags into an estimate of biological age. "Epigenetic age acceleration" means the estimate is older than the person's actual age.

The team searched six databases for studies from January 1, 2011 to April 15, 2026. They screened 42,023 records. The studies looked at all-cause dementia, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Participants were 60.5% female. The median of the studies' average ages was 69.4 years.

In the longitudinal analyses, which follow people over time, only one clock showed a clear link to dementia. Higher GrimAge acceleration was associated with higher dementia risk. The hazard ratio was 1.11 per standard deviation (95% confidence interval 1.02 to 1.20; p = 0.018). In plain terms, that is about 11% higher risk for each step up on the scale, and the range of plausible values runs from a very small increase to about 20%.

Four other measures were not significantly associated with dementia risk: Horvath1, Hannum, PhenoAge and DunedinPACE. The authors say GrimAge was the only DNA methylation age measure that consistently predicted higher all-cause dementia risk.

Results for the other neurodegenerative diseases were mixed. The evidence varied across clock generations and study designs. Mendelian randomization, a method that uses genetic variation to probe cause and effect, gave limited evidence that faster epigenetic aging drives these diseases.

The authors conclude that the clocks show limited and inconsistent associations with neurodegenerative disease. They say this is insufficient support for using them as disease biomarkers.

For anyone weighing a consumer epigenetic age test, the message from this analysis is cautious. A group-level link, as seen with GrimAge, is not the same as a reliable prediction for one person. It also does not say which commercial tests use which clocks, so that is unverified.

The authors call for disease-specific clocks that are independently validated. They also want pathway analyses to show which methylation changes relate to neurodegeneration and what biology they reflect. Watch for peer review of this preprint and for tests of newer, dementia-specific clocks.

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