Epigenetic g predicts cognitive function in a diverse, nationally representative sample of older adults.

Alzheimer's disease and related dementias (ADRD) are major public health concerns. DNA methylation (DNAm)-based biomarkers such as GrimAge and PhenoAge predict aging and health risk, but were not designed to optimize prediction of cognitive function or decline. Epigenetic g-a DNAm-derived index of general cognitive ability-is a promising marker of cognitive function that has not been assessed in a racially and socioeconomically diverse population. We used data from the 2016 Venous Blood Study of the Health and Retirement Study (HRS), a nationally representative cohort of U.S. adults aged ≥ 51 years (N = 3575 with high-quality DNAm). Epigenetic g scores were computed using CpG weights from a BayesR+ model of general cognitive ability developed in Generation Scotland. Cognitive function was measured with a modified version of the Telephone Interview for Cognitive Status (TICS) at each interview wave. Linear regression estimated associations with cognitive scores; mixed-effect growth curve models estimated the association with cognitive change. Models were adjusted sequentially for demographics, education, parental education, APOE ε4 status, and blood-based neurodegeneration markers (NfL, GFAP, Aβ42/40, pTau181). Higher epigenetic g was associated with better baseline cognition (β = 2.55, 95% CI 1.80-3.30)) and cognition at the time DNAm was measured (β = 2.30, 95% CI 1.47-3.13) after demographic adjustment. Associations were attenuated but remained significant with education and parental education (β = 1.23-1.89). In growth curve models, Epigenetic g was associated with higher cognitive performance but did not have a statistically significant association with decline over a 6-year period. Results were robust to adjustment for APOE ε4 and neurodegeneration biomarkers. Epigenetic g is a scalable, blood-based marker of cognitive function, and potentially or cognitive reserve, that adds predictive value beyond demographics, socioeconomic indicators, APOE, and neuropathology. Its validation in a diverse, nationally representative U.S. cohort underscores its potential for early risk profiling and for research on social determinants of cognitive aging in cross-national samples.