AIM: The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. METHODS: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. RESULTS: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. CONCLUSION: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging.. The study was funded by the National Institute of Health Research (NIHR) Academic Clinical Fellowship programme (ACF; LC) the Oxfordshire Health Services Research Committee (OHSRC; LC), the Oxford University Clinical Academic Graduate School (OUCAGS; LC), the UK Medical Research Council (G1001354; KPE; K013351; MK), the Gordon Edward Small’s Charitable Trust (SC008962; KPE), the HDH Wills 1965 charitable trust (charity No: 1117747; KPE), the Medical Research Council (MRC) (Grant number: MR/N027973/1; KL, EP) as part of the Joint Programme—Neurodegenerative Disease Research (JPND) grant for the EPI-AD consortium
