Epigenetic g predicts cognitive aging and incident dementia in a diverse, nationally representative sample of older adults

BackgroundAlzheimers 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 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. MethodsWe 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; 6-year incident dementia was defined using the validated Langa-Weir algorithm. Linear regression estimated associations with cognitive scores; logistic regression estimated 4-year dementia risk. Models were adjusted sequentially for demographics, education, parental education, APOE {varepsilon}4 status, and blood-based neurodegeneration markers (NfL, GFAP, A{beta}42/40, pTau181). ResultsHigher epigenetic g was associated with better baseline cognition ({beta}=2.55, 95% CI 1.92-3.17) and cognition at the time DNAm was measured ({beta}=2.30, 95% CI 1.62-2.99) after demographic adjustment. Associations attenuated but remained significant with education and parental education ({beta}=1.23-1.89). Each unit increase in epigenetic g predicted 29% lower 6-year risk of dementia (fully adjusted HR=0.71). Results were robust to adjustment for APOE {varepsilon}4 and neurodegeneration biomarkers. ConclusionsEpigenetic g is a scalable, blood-based marker of cognitive function and dementia risk 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.