Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

Background Cognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. Methods We performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. Results We found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10−7) that was robust to adjustment for cell type proportions (p = 8.52 × 10−7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10−6) and working (p = 2.54 × 10−7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology. Conclusions Differential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer’s disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer’s disease.