科研之友
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摘要
BackgroundCognitive trajectory varies widely and can distinguish those that develop dementia from those that remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. Here, we sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human post-mortem brain.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 = 9.96 x 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 even significant in participants with no or little signs of beta-amyloid and neurofibrillary tangle pathology.ConclusionsDifferential methylation of CLDN5, an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer Disease (AD) pathologies. The association between CLDN5 and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and AD.
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单位new; emory university; Columbia University Medical Center; Emory University School of Medicine; Emory university school of medicine; EMORY UNIVERSITY; emory university school of medicine
