Blood DNA Methylation Signature for Incident Dementia: Evidence from Longitudinal Cohorts.

Introduction: Distinguishing between molecular changes that precede dementia onset and those resulting from the disease is challenging with cross-sectional studies.

Methods: We studied blood DNA methylation (DNAm) differences and incident dementia in two large longitudinal cohorts: the Offspring cohort of the Framingham Heart Study (FHS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. We analyzed blood DNAm samples from over 1,000 cognitively unimpaired subjects.

Results: Meta-analysis identified 44 CpGs and 44 differentially methylated regions consistently associated with time to dementia in both cohorts. Our integrative analysis identified early processes in dementia, such as immune responses and metabolic dysfunction. Furthermore, we developed a Methylation-based Risk Score, which successfully predicted future cognitive decline in an independent validation set, even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score.

Discussion: DNA methylation offers a promising source of biomarker for early detection of dementia.