{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:55:21Z","timestamp":1790654121176,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000030","name":"Centers for Disease Control and Prevention","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Metformin, the first\u2010line treatment for Type 2 diabetes mellitus (T2DM), may be neuroprotective but also lowers serum vitamin B12 by ~19%, raising concern that B12 depletion could offset this benefit. We used modern exploratory causal mediation methods in a nationally representative sample to test whether vitamin B12 and methylmalonic acid (MMA) mediate the metformin\u2013cognition association.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>We analysed NHANES 2011\u20132014 data from 587 adults aged \u2265\u200960\u2009years with T2DM (408 metformin users, 179 users of other non\u2010insulin antidiabetics), using an active\u2010comparator design. The primary outcome was the Digit Symbol Substitution Test (DSST). Exploratory mediation analysis across four frameworks (bootstrap, parallel mediation, structural equation modeling, weighted quantile sum regression) tested whether B12 and MMA mediate the metformin\u2013cognition association, supplemented by sensitivity, quantile regression, causal forest and Bayesian analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Metformin users had lower serum B12 (569.3 vs. 825.3\u2009pg\/mL;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.026) but better cognitive performance (DSST 47.5 vs. 39.5;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Fully adjusted regression showed a 3.75\u2010point higher DSST score with metformin (95% CI \u22120.06 to 7.55;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.053), significant under multiple imputation (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20093.49;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.006). Across mediation frameworks, 95.1% of the effect was direct and B12\/MMA\u2010independent. Benefit was concentrated in adults aged 60\u201369\u2009years (interaction\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003) and lower DSST quantiles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Metformin is associated with better cognition in older T2DM adults. The association was not statistically explained by B12 or MMA. The benefit was concentrated in younger\u2010old and cognitively vulnerable subgroups.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71396","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:05:48Z","timestamp":1790651148000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Use Is Associated With Better Cognitive Performance in Older Adults With Type 2 Diabetes: Exploratory Analysis of Vitamin\n                    <scp>B12<\/scp>\n                    and Methylmalonic Acid Pathways in\n                    <scp>NHANES<\/scp>\n                    2011\u20132014"],"prefix":"10.1111","author":[{"given":"Danial","family":"Fotros","sequence":"first","affiliation":[{"name":"Neurobiology of Nutrition Laboratory, Department of Nutritional Sciences College of Health &amp; Human Sciences, Texas Tech University  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanieh","family":"Sakhdari","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Babol University of Medical Sciences  Babol Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4748-5135","authenticated-orcid":false,"given":"Andrew C.","family":"Shin","sequence":"additional","affiliation":[{"name":"Neurobiology of Nutrition Laboratory, Department of Nutritional Sciences College of Health &amp; Human Sciences, Texas Tech University  Lubbock Texas USA"},{"name":"Human Molecular Aging Center, Texas Tech University  Lubbock Texas USA"},{"name":"Center of Excellence for Translational Neuroscience &amp; Therapeutics, Texas Tech University Health Sciences Center  Lubbock Texas USA"},{"name":"Center of Excellence for Integrated Health, Texas Tech University Health Sciences Center  Lubbock Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2025.1624472","article-title":"A Review of Type 2 Diabetes Mellitus and Cognitive Impairment","volume":"16","author":"Kan W.","year":"2025","journal-title":"Frontiers in Endocrinology"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.2147\/CIA.S48926","article-title":"Type 2 Diabetes as a Risk Factor for Cognitive Impairment: Current Insights","volume":"9","author":"Umegaki H.","year":"2014","journal-title":"Clinical Interventions in Aging"},{"issue":"2","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.2337\/dc15-1588","article-title":"Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia","volume":"39","author":"Chatterjee S.","year":"2016","journal-title":"Diabetes Care"},{"issue":"16","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1001\/jama.2021.4001","article-title":"Association Between Age at Diabetes Onset and Subsequent Risk of Dementia","volume":"325","author":"Barbiellini Amidei C.","year":"2021","journal-title":"Journal of the American Medical Association"},{"issue":"9","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.2337\/dc24-0203","article-title":"Age of Diabetes Diagnosis and Lifetime Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study","volume":"47","author":"Hu J.","year":"2024","journal-title":"Diabetes Care"},{"issue":"1","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2991\/jegh.k.191028.001","article-title":"Epidemiology of Type 2 Diabetes \u2013 Global Burden of Disease and Forecasted Trends","volume":"10","author":"Khan M. 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