{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:38:39Z","timestamp":1786358319969,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Epidemiology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"award":["U01 DK048489"],"award-info":[{"award-number":["U01 DK048489"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048339"],"award-info":[{"award-number":["U01 DK048339"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048377"],"award-info":[{"award-number":["U01 DK048377"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048349"],"award-info":[{"award-number":["U01 DK048349"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048381"],"award-info":[{"award-number":["U01 DK048381"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048468"],"award-info":[{"award-number":["U01 DK048468"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048434"],"award-info":[{"award-number":["U01 DK048434"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048485"],"award-info":[{"award-number":["U01 DK048485"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048375"],"award-info":[{"award-number":["U01 DK048375"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048514"],"award-info":[{"award-number":["U01 DK048514"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048437"],"award-info":[{"award-number":["U01 DK048437"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U01 DK048413"],"award-info":[{"award-number":["U01 DK048413"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048411"],"award-info":[{"award-number":["U01 DK048411"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048406"],"award-info":[{"award-number":["U01 DK048406"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048380"],"award-info":[{"award-number":["U01 DK048380"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048397"],"award-info":[{"award-number":["U01 DK048397"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048412"],"award-info":[{"award-number":["U01 DK048412"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048404"],"award-info":[{"award-number":["U01 DK048404"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048387"],"award-info":[{"award-number":["U01 DK048387"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048407"],"award-info":[{"award-number":["U01 DK048407"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048443"],"award-info":[{"award-number":["U01 DK048443"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["U01 DK048400"],"award-info":[{"award-number":["U01 DK048400"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Metformin may influence risk of dementia, with prior conflicting observations of protection or harm.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design, Setting &amp; Participants<\/jats:title>\n                  <jats:p>Prospective long-term follow-up of DPP\/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposures<\/jats:title>\n                  <jats:p>Randomization to metformin, placebo, or ILS (1996\u20131999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes &amp; Measures<\/jats:title>\n                  <jats:p>Cognitive impairment syndromes were adjudicated in 2022\u2013 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer\u2019s Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Total metformin exposure (mean \u00b1 SD) was 15.5 \u00b17.7 years\/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 \u00b15.1 and 3.8 \u00b14.8 years\/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-\u03b54 genotype. Randomization to metformin was also associated with significantly better memory performance over time (\u03b2=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen\u2019s d=0.1).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>KEY POINTS<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>Is chronic metformin treatment related to the risk of dementia and cognitive impairment?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>Chronic metformin treatment may decrease the risk of dementia.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.05.26359234","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:40:14Z","timestamp":1786120814000},"source":"Crossref","is-referenced-by-count":0,"title":["Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-1464","authenticated-orcid":false,"given":"Pandora L.","family":"Wander","sequence":"first","affiliation":[{"name":"Veterans Affairs (VA) Puget Sound Health Care System and Department of Medicine, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-0422","authenticated-orcid":false,"given":"Lindsay","family":"Doherty","sequence":"additional","affiliation":[{"name":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1253-0490","authenticated-orcid":false,"given":"Qing","family":"Pan","sequence":"additional","affiliation":[{"name":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0576-0047","authenticated-orcid":false,"given":"Owen","family":"Carmichael","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Center, Pennington Biomedical Research Center, Baton Rouge, LA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7534-2935","authenticated-orcid":false,"given":"Raymond","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Neurology, MedStar Georgetown University Hospital and Georgetown University Medical Center, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6207-8792","authenticated-orcid":false,"given":"Shihchen","family":"Kuo","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6917-4197","authenticated-orcid":false,"given":"Medha","family":"Munshi","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3183-4062","authenticated-orcid":false,"given":"Amisha","family":"Wallia","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0648-6702","authenticated-orcid":false,"given":"James M.","family":"Noble","sequence":"additional","affiliation":[{"name":"Department of Neurology, Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, and the GH Sergievsky Center, Columbia University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-4057","authenticated-orcid":false,"given":"Vallabh O.","family":"Shah","sequence":"additional","affiliation":[{"name":"School of Medicine, Int Medicine, University of New Mexico HSC, Albuquerque, NM, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4363-1553","authenticated-orcid":false,"given":"Neelesh K.","family":"Nadkarni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Geriatric Medicine and Gerontology, and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-7771","authenticated-orcid":false,"given":"Sunder","family":"Mudaliar","sequence":"additional","affiliation":[{"name":"Diabetes\/Metabolism Section, VA San Diego HealthCare System; Clinical Professor of Medicine, University of California at San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9514-8929","authenticated-orcid":false,"given":"Dana","family":"Dabelea","sequence":"additional","affiliation":[{"name":"Departments of Epidemiology and Pediatrics, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-745X","authenticated-orcid":false,"given":"Marinella","family":"Temprosa","sequence":"additional","affiliation":[{"name":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7004-5197","authenticated-orcid":false,"given":"William C.","family":"Knowler","sequence":"additional","affiliation":[{"name":"Consultant, Biostatistics Center, George Washington University, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-2650","authenticated-orcid":false,"given":"David M.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-3648","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Luchsinger","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the DPP Research Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081003250566000_2026.08.05.26359234v1.1","doi-asserted-by":"publisher","DOI":"10.2337\/dc26-S009"},{"key":"2026081003250566000_2026.08.05.26359234v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.945609"},{"key":"2026081003250566000_2026.08.05.26359234v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012512"},{"key":"2026081003250566000_2026.08.05.26359234v1.4","doi-asserted-by":"publisher","DOI":"10.2337\/dc25-0014"},{"key":"2026081003250566000_2026.08.05.26359234v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61457-4"},{"key":"2026081003250566000_2026.08.05.26359234v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(25)00022-1"},{"key":"2026081003250566000_2026.08.05.26359234v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00191"},{"key":"2026081003250566000_2026.08.05.26359234v1.8","doi-asserted-by":"publisher","DOI":"10.3233\/jad-240495"},{"key":"2026081003250566000_2026.08.05.26359234v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2012.03916.x"},{"key":"2026081003250566000_2026.08.05.26359234v1.10","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0229"},{"key":"2026081003250566000_2026.08.05.26359234v1.11","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004586"},{"key":"2026081003250566000_2026.08.05.26359234v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/dme.14821"},{"key":"2026081003250566000_2026.08.05.26359234v1.13","doi-asserted-by":"publisher","DOI":"10.3233\/jad-150493"},{"key":"2026081003250566000_2026.08.05.26359234v1.14","doi-asserted-by":"publisher","DOI":"10.1097\/wad.0000000000000202"},{"key":"2026081003250566000_2026.08.05.26359234v1.15","doi-asserted-by":"publisher","DOI":"10.2337\/dci25-0032"},{"key":"2026081003250566000_2026.08.05.26359234v1.16","doi-asserted-by":"publisher","DOI":"10.1097\/WAD.0000000000000223"},{"key":"2026081003250566000_2026.08.05.26359234v1.17","doi-asserted-by":"publisher","DOI":"10.64898\/2026.07.17.26357765"},{"key":"2026081003250566000_2026.08.05.26359234v1.18","doi-asserted-by":"publisher","DOI":"10.64898\/2026.07.15.26357456"},{"key":"2026081003250566000_2026.08.05.26359234v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3956(82)90033-4"},{"key":"2026081003250566000_2026.08.05.26359234v1.20","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.48.5_suppl_6.10s"},{"key":"2026081003250566000_2026.08.05.26359234v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/37.3.323"},{"key":"2026081003250566000_2026.08.05.26359234v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2015.03.003"},{"key":"2026081003250566000_2026.08.05.26359234v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.008"},{"key":"2026081003250566000_2026.08.05.26359234v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.005"},{"key":"2026081003250566000_2026.08.05.26359234v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105405"},{"key":"2026081003250566000_2026.08.05.26359234v1.26","unstructured":"Wechsler D . Wechsler Adult Intelligence Scale-Revised. Psychological Corporation; 1988."},{"key":"2026081003250566000_2026.08.05.26359234v1.27","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617701755026"},{"key":"2026081003250566000_2026.08.05.26359234v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60461-5"},{"key":"2026081003250566000_2026.08.05.26359234v1.29","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.12923"},{"key":"2026081003250566000_2026.08.05.26359234v1.30","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.39723"},{"key":"2026081003250566000_2026.08.05.26359234v1.31","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-2376"},{"key":"2026081003250566000_2026.08.05.26359234v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/alz.71214"},{"key":"2026081003250566000_2026.08.05.26359234v1.33","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-1399"},{"key":"2026081003250566000_2026.08.05.26359234v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"2026081003250566000_2026.08.05.26359234v1.35","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199001000-00010"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.05.26359234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:25:16Z","timestamp":1786357516000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.08.05.26359234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":35,"URL":"https:\/\/doi.org\/10.64898\/2026.08.05.26359234","relation":{},"subject":[],"published":{"date-parts":[[2026,8,7]]},"subtype":"preprint"}}