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 > 1000 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, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini-Mental State Examination score.

DISCUSSION: DNAm offers a promising source as a biomarker for dementia risk assessment.

HIGHLIGHTS: Blood DNA methylation (DNAm) differences at individual CpGs and differentially methylated regions are significantly associated with incident dementia. Pathway analysis revealed DNAm differences associated with incident dementia are significantly enriched in biological pathways involved in immune responses and metabolic processes. Out-of-sample validation analysis demonstrated that a methylation-based risk score successfully predicted future cognitive decline in an independent dataset, even after accounting for age, sex, apolipoprotein E ε4, years of education, baseline diagnosis, and baseline Mini-Mental State Examination score.