Development and validation of MethylCog, a blood DNA methylation proxy for cognition.

INTRODUCTION: Heterogeneity in cognitive ability increases with age and predicts mild cognitive impairment (MCI) and dementia, but scalable blood-based biomarkers are lacking. We developed and validated MethylCog, a parsimonious DNA methylation (DNAm) marker of general cognitive ability (g).

METHODS: MethylCog was developed using elastic net regression on principal components analysis (PCA) -derived g in a population-based cohort (n = 2,069; training/test split) externally validated (n = 112). Criterion validity, MCI discrimination, and specificity relative to GrimAge and Alzheimer's disease (AD) biomarkers were assessed.

RESULTS: MethylCog (29 CpGs) predicted g in the test set (R = 0.17) and external cohort (R = 0.13), explaining ∼11% of variance beyond age and sex. MethylCog improved MCI discrimination beyond demographics (ΔAUC = 0.03-0.07) and outperformed GrimAge but did not add value beyond cognitive screeners. Exploratory analyses showed no significant associations with AD plasma biomarkers or MRI measures.

DISCUSSION: MethylCog provides initial evidence that parsimonious DNAm scores can index individual differences in cognitive ability, with potential utility where direct assessment is unavailable.