{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:28:24Z","timestamp":1791307704376,"version":"4.3.1"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) and mild cognitive impairment (MCI) are major causes of cognitive decline. Antidiabetic medications such as metformin, pioglitazone, and GLP-1 receptor agonists have been proposed as potential neuroprotective therapies. We assessed whether these agents slow cognitive decline or disease progression in people with AD or MCI. PubMed, Embase, and Cochrane Central were searched for randomized controlled trials and observational studies of metformin, pioglitazone, or GLP-1 receptor agonists in AD\/MCI. Results were synthesized narratively by drug class. Eleven studies met the inclusion criteria. Metformin, particularly in early-stage disease and metabolically vulnerable groups, demonstrated improvements in episodic memory and selective executive outcomes. Observational data in diabetic MCI suggested improved cognition and preservation of hippocampal and cortical structure, with limited amyloid-\u03b2 and tau changes. Pioglitazone findings varied. Benefits were mainly reported in mild AD with type-2 diabetes, but not in non-diabetic AD\/MCI. GLP-1 receptor agonists demonstrated preserved cerebral glucose metabolism and improved blood-to-brain glucose transport but did not improve cognitive function. Current evidence does not support antidiabetic therapies as effective treatments in AD\/MCI. Any benefits appear to depend on disease stage and metabolic status, with metformin being the most promising candidate. Larger, longer-duration biomarker-defined trials are needed to determine whether any sustained clinical benefit is observed.<\/jats:p>","DOI":"10.3390\/ijms27093967","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:22Z","timestamp":1777469542000},"page":"3967","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Antidiabetic Therapies in Mild Cognitive Impairment and Alzheimer\u2019s Disease: A Systematic Review of Metformin, Pioglitazone, and GLP-1 Receptor Agonists"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3090-5803","authenticated-orcid":false,"given":"Dina A.","family":"Mahoon","sequence":"first","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Hamad","sequence":"additional","affiliation":[{"name":"Research Department, Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-3917","authenticated-orcid":false,"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1177\/13872877251360221","article-title":"The global, regional, and national burden and attributable risk factors of Alzheimer\u2019s disease and other dementias, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study","volume":"107","author":"Yin","year":"2025","journal-title":"J. Alzheimers Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a006239","DOI":"10.1101\/cshperspect.a006239","article-title":"Epidemiology of Alzheimer disease","volume":"2","author":"Mayeux","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hao, M., and Chen, J. (2025). Trend analysis and future predictions of global burden of Alzheimer\u2019s disease and other dementias: A study based on the global burden of disease database from 1990 to 2021. BMC Med., 23.","DOI":"10.1186\/s12916-025-04169-w"},{"key":"ref_4","unstructured":"Alzheimer\u2019s Association (2025). 2025 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 21, e70235."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s00415-018-9108-0","article-title":"Predicting progression to Alzheimer\u2019s disease in subjects with amnestic mild cognitive impairment using performance on recall and recognition tests","volume":"266","author":"Perri","year":"2019","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3233\/JAD-150956","article-title":"Specific features of subjective cognitive decline predict faster conversion to mild cognitive impairment","volume":"52","author":"Medina","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Morat\u00f3, X., Pytel, V., Jofresa, S., Ruiz, A., and Boada, M. (2022). Symptomatic and disease-modifying therapy pipeline for Alzheimer\u2019s disease: Towards a personalized polypharmacology patient-centered approach. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169305"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1080\/14656566.2016.1258060","article-title":"Beyond immunotherapy: New approaches for disease modifying treatments for early Alzheimer\u2019s disease","volume":"17","author":"Ruthirakuhan","year":"2016","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Darwish, R., Alcibahy, Y., Bucheeri, S., Albishtawi, A., Tama, M., Shetty, J., and Butler, A.E. (2024). The role of hypothalamic microglia in the onset of insulin resistance and type 2 diabetes: A neuro-immune perspective. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252313169"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s11011-025-01700-z","article-title":"From metabolic dysregulation to neurodegenerative pathology: The role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer\u2019s disease","volume":"40","author":"Raza","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/ncpneuro0124","article-title":"Therapy insight: Type 2 diabetes mellitus and the risk of late-onset Alzheimer\u2019s disease","volume":"2","author":"Haan","year":"2006","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12967-021-02797-3","article-title":"Glucose excursions in type 2 diabetes modulate amyloid-related proteins associated with dementia","volume":"19","author":"Moin","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e002211","DOI":"10.1136\/bmjdrc-2021-002211","article-title":"Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia","volume":"9","author":"Moin","year":"2021","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1111\/jdi.12087","article-title":"Diabetes mellitus and risk of dementia: A meta-analysis of prospective observational studies","volume":"4","author":"Gudala","year":"2013","journal-title":"J. Diabetes Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Husain, K., Sarhan, S., Abdulla, A., Buhasan, A., Moin, A.S.M., and Butler, A.E. (2023). Dementia in diabetes: The role of hypoglycemia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129846"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/dom.14220","article-title":"Hypoglycaemia in type 2 diabetes exacerbates amyloid-related proteins associated with dementia","volume":"23","author":"Moin","year":"2021","journal-title":"Diabetes Obes. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"456","DOI":"10.2174\/1573399815666190129155654","article-title":"Pathophysiological mechanisms linking type 2 diabetes and dementia: Review of evidence from clinical, translational and epidemiological research","volume":"15","year":"2019","journal-title":"Curr. Diabetes Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"970","DOI":"10.14336\/AD.2021.1213","article-title":"Metformin\u2019s mechanisms in attenuating hallmarks of aging and age-related disease","volume":"13","author":"Cheng","year":"2022","journal-title":"Aging Dis."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kruczkowska, W., Ga\u0142\u0119ziewska, J., Buczek, P., P\u0142uciennik, E., Kciuk, M., and \u015aliwi\u0144ska, A. (2025). Overview of metformin and neurodegeneration: A comprehensive review. Pharmaceuticals, 18.","DOI":"10.3390\/ph18040486"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.2147\/JIR.S436147","article-title":"The role and mechanism of metformin in inflammatory diseases","volume":"16","author":"Lin","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/13543784.2017.1265504","article-title":"Pioglitazone for the treatment of Alzheimer\u2019s disease","volume":"26","author":"Galimberti","year":"2016","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6479","DOI":"10.36922\/an.6479","article-title":"Central role of PPAR\u03b3 in Alzheimer\u2019s disease: From pathophysiology to potential therapies","volume":"3","author":"Mohanty","year":"2025","journal-title":"Adv. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1093\/brain\/awh452","article-title":"Acute treatment with the PPAR\u03b3 agonist pioglitazone and ibuprofen reduces glial inflammation and A\u03b21\u201342 levels in APPV717I transgenic mice","volume":"128","author":"Heneka","year":"2005","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1073\/pnas.0503839103","article-title":"Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma","volume":"103","author":"Sastre","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Grieco, M., Giorgi, A., Gentile, M.C., d\u2019Erme, M., Morano, S., Maras, B., and Filardi, T. (2019). Glucagon-like peptide-1: A focus on neurodegenerative diseases. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01112"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Moaket, O.S., Obaid, S.E., Obaid, F.E., Shakeeb, Y.A., Elsharief, S.M., Tania, A., Darwish, R., Butler, A.E., and Moin, A.S.M. (2025). GLP-1 and the degenerating brain: Exploring mechanistic insights and therapeutic potential. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110743"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuropharm.2013.08.005","article-title":"Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP\/PS1 mice, a model of Alzheimer\u2019s disease","volume":"76","author":"McClean","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s11154-014-9285-9","article-title":"GLP-1R activation for the treatment of stroke: Updating and future perspectives","volume":"15","author":"Darsalia","year":"2014","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/0271678X20952011","article-title":"Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: A systematic scoping review","volume":"41","author":"Maskery","year":"2021","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/ana.23956","article-title":"Amylin deposition in the brain: A second amyloid in Alzheimer disease?","volume":"74","author":"Jackson","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gejl, M., Gjedde, A., Egefjord, L., M\u00f8ller, A., Hansen, S.B., Vang, K., Rodell, A., Br\u00e6ndgaard, H., Gottrup, H., and Schacht, A. (2016). In Alzheimer\u2019s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: Randomized, placebo-controlled, double-blind clinical trial. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00108"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17490","DOI":"10.1038\/s41598-017-17718-y","article-title":"Blood-brain glucose transfer in Alzheimer\u2019s disease: Effect of GLP-1 analog treatment","volume":"7","author":"Gejl","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3233\/JAD-150493","article-title":"Metformin in amnestic mild cognitive impairment: Results of a pilot randomized placebo controlled clinical trial","volume":"51","author":"Luchsinger","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/WAD.0000000000000202","article-title":"Effects of the insulin sensitizer metformin in Alzheimer disease","volume":"31","author":"Koenig","year":"2017","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_36","first-page":"1889","article-title":"Diabetic patients treated with metformin during early stages of Alzheimer\u2019s disease show a better integral performance: Data from the ADNI study","volume":"34","author":"Pomilio","year":"2022","journal-title":"Geroscience"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.3233\/JAD-230899","article-title":"Effect of metformin on plasma and cerebrospinal fluid biomarkers in non-diabetic older adults with mild cognitive impairment related to Alzheimer\u2019s disease","volume":"99","author":"Weinberg","year":"2024","journal-title":"J. Alzheimers Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.neurobiolaging.2009.10.009","article-title":"Efficacy of PPAR-\u03b3 agonist pioglitazone in mild Alzheimer disease","volume":"32","author":"Sato","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1001\/archneurol.2010.229","article-title":"A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease","volume":"68","author":"Geldmacher","year":"2011","journal-title":"Arch. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2174\/1567205016666190913155950","article-title":"A pilot study of exenatide actions in Alzheimer\u2019s disease","volume":"16","author":"Mullins","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1007\/s40618-024-02320-7","article-title":"Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: A proof-of-concept clinical trial","volume":"47","author":"Cas","year":"2024","journal-title":"J. Endocrinol. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000371509","article-title":"Effects of pioglitazone or exercise in older adults with mild cognitive impairment and insulin resistance: A pilot study","volume":"5","author":"Hildreth","year":"2015","journal-title":"Dement. Geriatr. Cogn. Disord. Extra"},{"key":"ref_43","first-page":"277","article-title":"Antidiabetic drugs and their potential role in treating mild cognitive impairment and Alzheimer\u2019s disease","volume":"16","author":"Alagiakrishnan","year":"2013","journal-title":"Discov. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3967\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:32:44Z","timestamp":1777469564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3967"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093967"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093967","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}