A blood DNA methylation marker of cognitive ability is associated with six-year cognitive performance independent of blood Alzheimer's disease biomarkers.

MethylCog is a 29-CpG blood DNA methylation (DNAm) score developed to index general cognitive ability (g). Whether it captures cognition-related information associated with later cognitive performance that is not fully represented by blood-based biomarkers of Alzheimer's disease and related dementias (ADRD) remains unclear. Using the held-out Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) test set from the original MethylCog study (N = 605), we examined associations with baseline g after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), and amyloid-β 42/40 ratio (Aβ42/40). Prospective associations with six-year follow-up g were examined after adjustment for baseline g, age, sex, education, and APOE ε4 carrier status, with additional adjustment for the ADRD biomarker panel. MethylCog remained associated with baseline g in the fully adjusted cross-sectional model (standardized β=.178, 95% CI: .111-.244, p<.001; ΔAdjR²=.025). MethylCog was also associated with six-year follow-up g after adjustment for baseline g and all covariates and biomarkers (standardized β=.101, 95% CI: .033-.170, p=.004; N = 331; ΔAdjR²=.007). Findings were similar among participants without baseline cognitive impairment. These findings provide preliminary evidence that a cognition-trained DNAm signature captures variation in later cognitive performance not fully represented by baseline cognition or available ADRD blood biomarkers.