{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:46:33Z","timestamp":1792122393852,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R35AG71476"],"award-info":[{"award-number":["R35AG71476"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RO1NS139383"],"award-info":[{"award-number":["RO1NS139383"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021066","name":"Gates Ventures","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is the leading cause of dementia in older individuals and remains a major clinical and socioeconomic burden. Despite the success of anti\u2010amyloid therapies in reducing biomarker burden, more effective and safer treatments are still needed. Given the emerging evidence of a role for metabolic dysfunction and brain insulin resistance in AD pathophysiology, glucagon\u2010like peptide\u20101 receptor agonists (GLP\u20101 RAs) have been proposed as potential disease\u2010modifying therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We conducted a systematic review and meta\u2010analysis of PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to April 22, 2026 to evaluate the efficacy and safety of GLP\u20101 RAs in AD and mild cognitive impairment. Randomized controlled trials comparing GLP\u20101 RAs with placebo, standard care, or non\u2010intervention across the Alzheimer's continuum were eligible; abstracts and studies with unavailable results were excluded. Random\u2010effects models were used. Risk ratios (RRs) were calculated for binary outcomes, and mean or standardized mean differences for continuous outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Seven studies comprising 4132 participants met the inclusion criteria. The mean age of the pooled studies was 72.1 years, while the mean baseline Clinical Dementia Rating\u2014Sum of Boxes (CDR\u2010SB) varied from 2.71 to 3.8. GLP\u20101 RAs were not associated with significant improvement in cognition (Alzheimer's Disease Assessment Scale\u2013Cognitive Subscale: standard mean difference \u22120.05; 95% confidence interval [CI]: \u22120.12 to 0.02;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.1928) or disease progression (CDR\u2010SB: mean difference: 0.09; 95% CI: \u22120.10 to 0.28;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.362). They were associated with a higher frequency of adverse events (RR 1.07; 95% CI: 1.04 to 1.10;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001) and weight loss (RR 5.01; 95% CI: 3.99 to 6.27;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001). Biomarker and neuroimaging findings were inconsistent and failed to translate to clinical benefit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>GLP\u20101 RAs did not improve cognitive or functional outcomes in AD and were associated with adverse events. Their role may be better explored in biomarker\u2010enriched, metabolically selected populations or assessment of GLP\u20101 RAs with greater brain penetrance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70334","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:29:26Z","timestamp":1792121366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GLP\u20101 receptor agonists in Alzheimer's disease and MCI: a meta\u2010analysis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0385-0883","authenticated-orcid":false,"given":"Ryan G. P.","family":"Siqueira","sequence":"first","affiliation":[{"name":"Department of Medicine Federal University of Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Ranalli","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duygu","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Faculty of Medicine K\u00fctahya Health Sciences University  K\u00fctahya Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meire","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Medicine Universidad del Pacifico  Pedro Juan Caballero Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo Raposo Pinel","family":"Maltez","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Fluminense Federal University  Niter\u00f3i Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Gosch","family":"Berton","sequence":"additional","affiliation":[{"name":"School of Medicine University of Passo Fundo  Passo Fundo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Cummings","sequence":"additional","affiliation":[{"name":"Chambers\u2010Grundy Center for Transformative Neuroscience Department of Brain Health Kirk Kerkorian School of Medicine University of Nevada Las Vegas  Las Vegas Nevada USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/S0140-6736(25)01389-3","article-title":"Alzheimer's disease outlook: controversies and future directions","volume":"406","author":"Frisoni GB","year":"2025","journal-title":"Lancet"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global estimates on the number of persons across the Alzheimer's disease continuum","volume":"19","author":"Gustavsson A","year":"2023","journal-title":"Alzheimers Dement"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1474-4422(18)30403-4","article-title":"Global, regional, and national burden of Alzheimer's disease and other dementias, 1990\u20102016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Nichols E","year":"2019","journal-title":"Lancet Neurol"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1002\/gps.4965","article-title":"Bidirectional relationship between caregiver burden and neuropsychiatric symptoms in patients with Alzheimer's disease: a narrative review","volume":"34","author":"Isik AT","year":"2019","journal-title":"Int J Geriatr Psychiatry"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.neurot.2025.e00570","article-title":"Maximizing the benefit and managing the risk of anti\u2010amyloid monoclonal antibody therapy for Alzheimer's disease: strategies and research directions","volume":"22","author":"Cummings JL","year":"2025","journal-title":"Neurotherapeutics"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S1474-4422(20)30231-3","article-title":"Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches","volume":"19","author":"Kellar D","year":"2020","journal-title":"Lancet Neurol"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.2337\/db13-1954","article-title":"Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease","volume":"63","author":"De Felice FG","year":"2014","journal-title":"Diabetes"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S1474-4422(05)70284-2","article-title":"Risk of dementia in diabetes mellitus: a systematic review","volume":"5","author":"Biessels GJ","year":"2006","journal-title":"Lancet Neurol"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1205207","article-title":"Glucagon\u2010like peptide 1 (GLP\u20101) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta\u2010analysis of preclinical studies","volume":"14","author":"Kong F","year":"2023","journal-title":"Front Pharmacol"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1177\/13872877251351329","article-title":"Associations of semaglutide with Alzheimer's disease\u2010related dementias in patients with type 2 diabetes: a real\u2010world target trial emulation study","volume":"106","author":"Wang W","year":"2025","journal-title":"J Alzheimers Dis"},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/S0140-6736(26)00459-9","article-title":"Efficacy and safety of oral semaglutide 14\u00a0mg (flexible dose) in early\u2010stage symptomatic Alzheimer's disease (EVOKE and EVOKE+): two phase 3, randomised, placebo\u2010controlled trials","volume":"407","author":"Cummings JL","year":"2026","journal-title":"Lancet"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10072-025-08602-z","article-title":"The effect of GLP\u20101 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or Alzheimer's disease: a meta\u2010analysis of randomized controlled trials","volume":"47","author":"O'Mara A","year":"2026","journal-title":"Neurol Sci"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/pharmaceutics18010069","article-title":"Liraglutide and exenatide in Alzheimer's disease and mild cognitive impairment: a systematic review and meta\u2010analysis of cognitive outcomes","volume":"18","author":"Santos P","year":"2026","journal-title":"Pharmaceutics"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred reporting items for systematic reviews and meta\u2010analyses: the PRISMA statement","volume":"6","author":"Moher D","year":"2009","journal-title":"PLoS Med"},{"key":"e_1_2_11_16_1","unstructured":"HigginsJPT ThomasJ ChandlerJ et\u00a0al.Cochrane handbook for systematic reviews of interventions version 6.5.Cochrane;2024.www.cochrane.org\/handbook"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne JAC","year":"2019","journal-title":"BMJ"},{"key":"e_1_2_11_18_1","unstructured":"Sch\u00fcnemannH Bro\u017cekJ GuyattG OxmanA eds.GRADE handbook for grading quality of evidence and strength of recommendations.The GRADE Working Group;2013.guidelinedevelopment.org\/handbook"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41591-025-04106-7","article-title":"Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial","volume":"32","author":"Edison P","year":"2026","journal-title":"Nat Med"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1007\/s40618-024-02320-7","article-title":"Long\u2010acting exenatide does not prevent cognitive decline in mild cognitive impairment: a proof\u2010of\u2010concept clinical trial","volume":"47","author":"Dei Cas A","year":"2024","journal-title":"J Endocrinol Invest"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2174\/1567205016666190913155950","article-title":"A pilot study of exenatide actions in Alzheimer's disease","volume":"16","author":"Mullins RJ","year":"2019","journal-title":"Curr Alzheimer Res"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fnagi.2016.00108","article-title":"In Alzheimer's disease, 6\u2010month treatment with GLP\u20101 analog prevents decline of brain glucose metabolism: randomized, placebo\u2010controlled, double\u2010blind clinical trial","volume":"8","author":"Gejl M","year":"2016","journal-title":"Front Aging Neurosci"},{"key":"e_1_2_11_23_1","unstructured":"ClinicalTrials.gov.A research study looking at the effect of semaglutide on the immune system and other biological processes in people with Alzheimer's disease (NCT05891496). Accessed May 09 2026.https:\/\/clinicaltrials.gov\/study\/NCT05891496"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s43587-025-01029-3","article-title":"Repurposing glucagon\u2010like peptide\u20101 receptor agonists for the treatment of neurodegenerative disorders","volume":"6","author":"Sabbagh MN","year":"2025","journal-title":"Nat Aging"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41380-022-01792-4","article-title":"Incretin and insulin signaling as novel therapeutic targets for Alzheimer's and Parkinson's disease","volume":"28","author":"Nowell J","year":"2023","journal-title":"Mol Psychiatry"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer's disease","volume":"397","author":"Scheltens P","year":"2021","journal-title":"Lancet"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13195-024-01456-1","article-title":"Utilization of fluid\u2010based biomarkers as endpoints in disease\u2010modifying clinical trials for Alzheimer's disease: a systematic review","volume":"16","author":"Oosthoek M","year":"2024","journal-title":"Alzheimers Res Ther"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2337\/dc24-1678","article-title":"Efficacy of GLP\u20101 receptor agonists on weight loss, BMI, and waist circumference for patients with obesity or overweight: a systematic review, meta\u2010analysis, and meta\u2010regression of 47 randomized controlled trials","volume":"48","author":"Wong HJ","year":"2025","journal-title":"Diabetes Care"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s40266-017-0462-x","article-title":"Weight loss in patients with dementia: considering the potential impact of pharmacotherapy","volume":"34","author":"Franx BAA","year":"2017","journal-title":"Drugs Aging"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.3390\/nu15132927","article-title":"Prevalence of malnutrition in people with dementia in long\u2010term care: a systematic review and meta\u2010analysis","volume":"15","author":"Perry E","year":"2023","journal-title":"Nutrients"},{"key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3390\/jcm12010145","article-title":"Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP\u20101 receptor agonists: a multidisciplinary expert consensus","volume":"12","author":"Gorgojo\u2010Mart\u00ednez JJ","year":"2022","journal-title":"J Clin Med"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/obr.12805"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup","volume":"20","author":"Jack CR","year":"2024","journal-title":"Alzheimers Dement"},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"718","DOI":"10.14283\/jpad.2023.114","article-title":"Multimodal precision prevention\u2014a new direction in Alzheimer's disease","volume":"10","author":"Barbera M","year":"2023","journal-title":"J Prev Alzheimers Dis"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1002\/alz.12123","article-title":"World\u2010Wide FINGERS Network: a global approach to risk reduction and prevention of dementia","volume":"16","author":"Kivipelto M","year":"2020","journal-title":"Alzheimers Dement"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2023.123688"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114187"}],"container-title":["Alzheimer's &amp; Dementia: Translational Research &amp; Clinical Interventions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70334","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/trc2.70334","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/trc2.70334","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:29:33Z","timestamp":1792121373000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/trc2.70334"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/trc2.70334"],"URL":"https:\/\/doi.org\/10.1002\/trc2.70334","archive":["Portico"],"relation":{},"ISSN":["2352-8737","2352-8737"],"issn-type":[{"value":"2352-8737","type":"print"},{"value":"2352-8737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70334"}}