Multisite chronic pain is a risk factor for Alzheimer's disease, but its relationship with Alzheimer's pathology remains unclear. This study examines the association between multisite chronic pain and single-site chronic pain with cognitive decline and post-mortem Alzheimer's biomarkers in older adults. We conducted a longitudinal and prospective observational study using data from 3459 participants without dementia at baseline in the Religious Orders Study and Rush Memory and Aging Project. Participants (mean age = 77.94, SD = 7.93 years) were followed for an average of 8.53 years (SD = 5.74), with cognitive assessments and post-mortem biomarker analyses in a subset of brain donors (n range from 863 to 987 based on assay quality and tissue preservation). Cognitive function was measured using repeated assessments of five cognitive domains and a global composite score. Chronic pain was classified based on self-reported pain, determined by the number of joint sites affected during the first two assessments: Multisite chronic pain was defined as chronic pain in more than one site, single-site chronic pain as chronic pain in one site, and no chronic pain as no chronic pain sites. Brain beta-amyloid (Aβ) load and tau tangle density were assessed post-mortem, ∼10 months after the last clinical evaluation. This was assessed as a global measure across eight Alzheimer's-affected brain regions, as well as specifically in the entorhinal cortex and hippocampus. Apolipoprotein-ɛ4 genotype was determined from blood and tissue samples. Compared to individuals with single-site (n = 506) or no chronic pain (n = 2599), participants with multisite chronic pain (n = 354) showed steeper declines in global cognition, episodic memory and working memory-especially among those with higher apolipoprotein-ɛ4 load-and were more likely to develop Alzheimer's dementia. Multisite chronic pain was also linked to increased Aβ deposition in the entorhinal cortex and hippocampus, particularly in apolipoprotein-ɛ4 carriers. Compared to people with no chronic pain, single-site chronic pain did not differ on rate of cognitive decline, Alzheimer's dementia risk or post-mortem Alzheimer's biomarkers. Multisite, but not single-site, chronic pain is linked to steeper cognitive decline and increased Aβ deposition, particularly in individuals with elevated Alzheimer's genetic risk. These findings suggest that reducing pain may mitigate the risk of cognitive decline and dementia.
Keywords: APOE ɛ4; Alzheimer’s risk; chronic pain; cognitive decline; older adults.
© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.