INTRODUCTION Dementia pose a significant public health challenge, especially as the population ages. Dementia cases are often underreported, highlighting the need to identify individuals at risk early. However, distinguishing between molecular changes that precede dementia onset and those resulting from the disease is challenging with cross-sectional studies. METHODS To address this, 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 FHS participants (n = 907) were followed for up to 7.72 years after blood sample collection at Exam 9; ADNI participants (n = 216) were followed for up to 11.11 years after their initial visits. The mean ages at sample collection were 72.03 years in FHS and 76.73 years in ADNI. Meta-analysis of results from Cox regression models 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. Validations with two independent datasets, the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study and the AddNeuroMed study, showed significant discriminatory classification of dementia samples versus controls using methylation risk scores based on the 44 dementia-associated CpGs. DISCUSSION These findings demonstrate that DNA methylation offers a promising pathway for early detection and prevention of dementia in at-risk populations.

The authors have declared no competing interest.

This research was supported by US National Institutes of Health grants R61NS135587 (L.W.), RF1NS128145 (L.W.), and R01AG062634 (E.R.M, B.W.K, L.W.).

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IRB of the University of Miami gave ethical approval for this work

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