{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:03:55Z","timestamp":1790762635498,"version":"4.1.0"},"reference-count":101,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer\u2019s disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson\u2019s disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.<\/jats:p>","DOI":"10.3390\/ijms27198738","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:25:42Z","timestamp":1790760342000},"page":"8738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity\u2013Neurodegeneration Interface: A Narrative Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2207-5129","authenticated-orcid":false,"given":"Elena","family":"Popa","sequence":"first","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"Department of Preventive Medicine and Interdisciplinarity, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, Universitatii Str. 16, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1622-2543","authenticated-orcid":false,"given":"Andrei Emilian","family":"Popa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"\u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinic Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2503-5395","authenticated-orcid":false,"given":"Vladimir","family":"Poroch","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"2nd Internal Medicine Department, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-4004","authenticated-orcid":false,"given":"Thomas Gabriel","family":"Schreiner","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"\u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinic Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Slanina","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"\u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinic Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Poroch","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"Department of Preventive Medicine and Interdisciplinarity, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, Universitatii Str. 16, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru Matei","family":"Hatneanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Iuliana","family":"Ungureanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"Department of Preventive Medicine and Interdisciplinarity, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, Universitatii Str. 16, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoneta Dacia","family":"Petroaie","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"\u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinic Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes Iacinta","family":"Bacusca","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"Department of Preventive Medicine and Interdisciplinarity, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, Universitatii Str. 16, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Adorata","family":"Coman","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cGrigore T. Popa\u201d University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania"},{"name":"\u201cProf. Dr. Nicolae Oblu\u201d Emergency Clinic Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD 2021 Nervous System Disorders Collaborators (2024). Global, Regional, and National Burden of Disorders Affecting the Nervous System, 1990\u20132021: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet Neurol., 23, 344\u2013381. Correction in Lancet Neurol. 2024, 23, e9. Correction in Lancet Neurol. 2024, 23, e11.","DOI":"10.1016\/S1474-4422(24)00231-X"},{"key":"ref_2","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2024). 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