Blood DNA Methylation Predicts Long-Term Risk of Dementia in Prospective Cohorts

Blood-based DNA methylation may help identify biological changes related to dementia risk before clinical symptoms appear. We conducted an epigenome-wide association study of incident all-cause dementia in 5,999 cognitively healthy women from the Women's Health Initiative Memory Study, 777 of whom developed dementia over up to 25 years of follow-up. Baseline blood DNA methylation was tested for association with time to dementia. One CpG site, cg05917797, was significantly associated with dementia risk, with higher methylation linked to lower risk. This association was only minimally changed after accounting for APOE ε4 carrier status, plasma p-tau217, and epigenetic aging measures. cg05917797 also replicated in meta-analysis of four independent prospective cohorts including 10,916 participants and 413 incident dementia cases. In post-mortem brain methylation datasets, higher methylation at cg05917797 was associated with lower Braak stage in temporal gyrus and cerebellum. In meta-analysis of all five prospective cohorts, including 16,915 participants and 1,190 dementia cases, cg05917797 remained the leading association, and three additional CpGs were identified for further study. These findings support cg05917797 as a reproducible blood-based epigenetic marker of long-term dementia risk.