Chronic pain-induced methylation in the prefrontal cortex targets gene networks associated with cognition and Alzheimer's disease.

Chronic pain is prevalent among aging adults. Epidemiologic evidence has demonstrated that individuals with chronic pain have accelerated memory decline and increased probability of dementia. Neurophysiologic, molecular, and pharmacologic hypotheses have been proposed to explain the relationship between chronic pain and cognitive decline, but there remains currently limited evidence supporting any of these. Here, we integrate multi-omic data across human cohorts and rodent species and demonstrate that methylation in the prefrontal cortex induced by chronic pain specifically targets transcriptional networks associated with cognitive ability, memory, and Alzheimer's disease in humans. We validate this with multiple independent data sets and identify cortical microglia as a likely mechanism by which chronic pain can increase dementia risk. Our analyses support the molecular hypothesis for the role of chronic pain in cognitive decline and identifies several potential therapeutic targets.