{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:13:37Z","timestamp":1792242817873,"version":"4.4.0"},"reference-count":66,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Neuroendocrinology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon\u2010like peptide\u20101 receptor agonists (GLP\u20101RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP\u20101RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP\u20101RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP\u20101 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.<\/jats:p>","DOI":"10.1111\/jne.70246","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T23:41:30Z","timestamp":1786491690000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>GLP<\/scp>\n                    \u20101 receptor agonists, metabolic syndrome, and Alzheimer's disease: Lessons and opportunities from the\n                    <scp>EVOKE<\/scp>\n                    trials"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3709-0670","authenticated-orcid":false,"given":"Pragati","family":"Gupta","sequence":"first","affiliation":[{"name":"Barts and The London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0556-0176","authenticated-orcid":false,"given":"Valeria","family":"Pozzilli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry Universit\u00e0 Campus Bio\u2010Medico di Roma  Rome Italy"},{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8839-9662","authenticated-orcid":false,"given":"Anastasia","family":"De Giovanni","sequence":"additional","affiliation":[{"name":"Department of Engineering Campus Bio\u2010Medico University  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Sapio","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry Universit\u00e0 Campus Bio\u2010Medico di Roma  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Motolese","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry Universit\u00e0 Campus Bio\u2010Medico di Roma  Rome Italy"},{"name":"Department of Neurology Fondazione Policlinico Universitario Campus Bio\u2010Medico  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fioravante","family":"Capone","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Unit of Neurology, Neurophysiology, Neurobiology and Psychiatry Universit\u00e0 Campus Bio\u2010Medico di Roma  Rome Italy"},{"name":"Department of Neurology Fondazione Policlinico Universitario Campus Bio\u2010Medico  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5090-636X","authenticated-orcid":false,"given":"Paolo","family":"Pozzilli","sequence":"additional","affiliation":[{"name":"Centre of Immunobiology The Blizard Institute, Queen Mary University of London  London UK"},{"name":"Unit of Thyroid and Metabolic Diseases University Campus Bio\u2010Medico  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1639896"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13439"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1590\/1980\u20105764\u2010dn\u20102023\u20100032"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70060"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1400589"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001931\u2010z"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010180263"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300\u2010024\u201001538\u20101"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010025\u201004106\u20107"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(26)00459\u20109"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25715"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.07.755"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666\u20107568(23)00019\u20103"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010024\u201001529\u20101"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220684120"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2501527122"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2018.06.014"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(15)70016\u20105"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.056"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1033479"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwab096"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc24\u20100203"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08\u20100586"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010019\u20100358\u20102"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010022\u201001024\u2010z"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1017\/S2045796020000347"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2025.0353"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020\u2010026\u201004581\u2010z"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2032183"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307563"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40120\u2010025\u201000724\u2010y"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph18050614"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1205207"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2024.102019"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp\u20102024\u2010335593"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2025.5684"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201066167\u2010z"},{"key":"e_1_2_12_39_1","unstructured":"Aarhus University Hospital.The Safety and Efficacy of Acute Subcutaneous Administration of Semaglutide in Non\u2010diabetic Patients With Acute Ischemic Stroke: A Multicentre Phase 2 Prospective Randomized Open\u2010label Blinded Endpoint Trial [Clinical trial registration] [Internet]. clinicaltrials.gov; 2023 Apr [cited 2026 Jul 10]. Clinical trial registration no.: NCT05630586. Available from:https:\/\/clinicaltrials.gov\/study\/NCT05630586"},{"key":"e_1_2_12_40_1","unstructured":"KruuseC.The Effect of Glucagon\u2010like Peptide 1 (GLP\u20101) Receptor Agonist on Cerebral Blood Flow Velocity in Non\u2010Stroke Volunteers (EGRABINS1) [Clinical trial registration] [Internet]. clinicaltrials.gov; 2017 Feb [cited 2026 Jul 10]. Clinical trial registration no.: NCT02838589. Available from:https:\/\/clinicaltrials.gov\/study\/NCT02838589"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.2217\/nmt.13.73"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.70058"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2025.21016"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2025.0360"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205016666190913155950"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114187"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010024\u201001537\u20101"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15638"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15603"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1210347"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11121647"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.38366"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.86628"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010019\u20100471\u20102"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semnuclmed.2013.06.003"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259\u2010011\u20101980\u20100"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.115.167445"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262110743"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S506957"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2025.177979"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.3390\/receptors4010002"},{"key":"e_1_2_12_62_1","volume-title":"Introduction to Mediation, Moderation, and Conditional Process Analysis: a Regression Based Approach","author":"Hayes AF","year":"2022"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010024\u201001666\u20107"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107927"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2025.114779"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc24\u2010SINT"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.231555"}],"container-title":["Journal of Neuroendocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jne.70246","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jne.70246","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jne.70246","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:01:02Z","timestamp":1788480062000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jne.70246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":66,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/jne.70246"],"URL":"https:\/\/doi.org\/10.1111\/jne.70246","archive":["Portico"],"relation":{},"ISSN":["0953-8194","1365-2826"],"issn-type":[{"value":"0953-8194","type":"print"},{"value":"1365-2826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-03-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70246"}}