Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

ObjectiveCognitive decline is a hallmark of dementia; however, the brain epigenetic signature of cognitive decline is unclear. We investigated the associations between brain tissue-based DNA methylation and cognitive trajectory.MethodsWe performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC). To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits (GAMuT) test to analyze the five measured cognitive domains simultaneously.ResultsWe found an epigenome-wide association for differential methylation of sites in the Claudin-5 (CLDN5) locus and cognitive trajectory (p-value x 9.96 × 10-7), which was robust to adjustment for cell type proportions (p-value = 8.52 x 10-7). This association was primarily driven by association with declines in episodic (p-value = 4.65 x 10-6) and working memory (p-value = 2.54 x 10-7). This association between methylation in CLDN5 and cognitive decline was independent of beta-amyloid and neurofibrillary tangle pathology and present in participants with low levels of neuropathology. In addition, only 13-31% of the association between methylation and cognitive decline was mediated through levels of neuropathology, whereas the major part of the association was independent of it.InterpretationWe identified methylation in CLDN5 as new epigenetic factor associated with cognitive trajectory. Higher levels of methylation in CLDN5 were associated with faster cognitive decline implicating the blood brain barrier in maintenance of cognitive trajectory.