Abstract
Molecular biomarkers of brain aging are needed to advance understanding of age-related neurodegeneration. We developed a highly accurate epigenetic biomarker of tissue age, the “epigenetic clock” based on DNA methylation levels. Here, we examine association between epigenetic age and Alzheimer’s disease (AD), cognitive decline, and AD-related neuropathology in 700 dorsolateral prefrontal cortex (DLPFC) samples from the Religious Order Study and Rush Memory and Aging Project. Results shows increased epigenetic age acceleration is associated with post-mortem AD diagnosis (P=0.009), increased neuropathology--neuritic plaques (P=0.0002), diffuse plaques (P=.046), Neurofibrillary tangles (P=0.009), and amyloid load (P=0.002)--and steeper declines in global cognitive functioning in the years leading up to their death (P=0.004). Results also suggest neuropathological markers mediate associations between epigenetic age and cognitive decline. Finally, genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration, diffuse plaques (r=0.24), and working memory (r=-0.35) may share a common genetic profile.