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This study examines the association between multisite chronic pain and single-site chronic pain with cognitive decline and post-mortem Alzheimer\u2019s 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 (A\u03b2) load and tau tangle density were assessed post-mortem, \u223c10 months after the last clinical evaluation. This was assessed as a global measure across eight Alzheimer\u2019s-affected brain regions, as well as specifically in the entorhinal cortex and hippocampus. Apolipoprotein-\u025b4 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\u2014especially among those with higher apolipoprotein-\u025b4 load\u2014and were more likely to develop Alzheimer\u2019s dementia. Multisite chronic pain was also linked to increased A\u03b2 deposition in the entorhinal cortex and hippocampus, particularly in apolipoprotein-\u025b4 carriers. Compared to people with no chronic pain, single-site chronic pain did not differ on rate of cognitive decline, Alzheimer\u2019s dementia risk or post-mortem Alzheimer\u2019s biomarkers. Multisite, but not single-site, chronic pain is linked to steeper cognitive decline and increased A\u03b2 deposition, particularly in individuals with elevated Alzheimer\u2019s genetic risk. These findings suggest that reducing pain may mitigate the risk of cognitive decline and dementia.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf208","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:01:16Z","timestamp":1748390476000},"source":"Crossref","is-referenced-by-count":13,"title":["Multisite chronic pain: association with cognitive decline and post-mortem Alzheimer\u2019s biomarkers"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5702-5995","authenticated-orcid":false,"given":"Tyler R","family":"Bell","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol E","family":"Franz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imanuel R","family":"Lerman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna E","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6527-6361","authenticated-orcid":false,"given":"Christine","family":"Fennema-Notestine","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S","family":"Panizzon","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5840-1769","authenticated-orcid":false,"given":"Jeremy A","family":"Elman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-554X","authenticated-orcid":false,"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-5609","authenticated-orcid":false,"given":"William S","family":"Kremen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego , San Diego, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"issue":"36","key":"2025061005065698900_fcaf208-B1","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.15585\/mmwr.mm6736a2","article-title":"Prevalence of chronic pain and high-impact chronic pain among adults\u2014United States, 2016","volume":"67","author":"Dahlhamer","year":"2018","journal-title":"MMWR Morb Mortal Wkly 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