{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T12:34:58Z","timestamp":1793450098474,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Novo Nordisk A\/S"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Alz Res Therapy"],"DOI":"10.1186\/s13195-024-01666-7","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T02:21:17Z","timestamp":1736302877000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":165,"title":["evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"17","author":[{"given":"Jeffrey L.","family":"Cummings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Atri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard H.","family":"Feldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip K.","family":"Knop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Johannsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Le\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Scheltens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"issue":"10284","key":"1666_CR1","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","volume":"397","author":"P Scheltens","year":"2021","unstructured":"Scheltens P, De Strooper B, Kivipelto M, Holstege H, Ch\u00e9telat G, Teunissen CE, et al. Alzheimer\u2019s disease. Lancet. 2021;397(10284):1577\u201390.","journal-title":"Lancet"},{"issue":"4","key":"1666_CR2","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer\u2019s disease. Lancet Neurol. 2015;14(4):388\u2013405.","journal-title":"Lancet Neurol"},{"issue":"3","key":"1666_CR3","doi-asserted-by":"publisher","first-page":"779","DOI":"10.3233\/JAD-180766","volume":"67","author":"JL Cummings","year":"2019","unstructured":"Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer\u2019s disease: current and future pharmacotherapy options. J Alzheimers Dis. 2019;67(3):779\u201394.","journal-title":"J Alzheimers Dis"},{"issue":"6","key":"1666_CR4","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1007\/s10787-021-00889-6","volume":"29","author":"R Dhapola","year":"2021","unstructured":"Dhapola R, Hota SS, Sarma P, Bhattacharyya A, Medhi B, Reddy DH. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer\u2019s disease. Inflammopharmacology. 2021;29(6):1669\u201381.","journal-title":"Inflammopharmacology"},{"issue":"7","key":"1666_CR5","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1038\/s41591-023-02380-x","volume":"29","author":"B Bellaver","year":"2023","unstructured":"Bellaver B, Povala G, Ferreira PCL, Ferrari-Souza JP, Leffa DT, Lussier FZ, et al. Astrocyte reactivity influences amyloid-\u03b2 effects on tau pathology in preclinical Alzheimer\u2019s disease. Nat Med. 2023;29(7):1775\u201381.","journal-title":"Nat Med"},{"issue":"4","key":"1666_CR6","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","volume":"54","author":"C Bellenguez","year":"2022","unstructured":"Bellenguez C, K\u00fc\u00e7\u00fckali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias. Nat Genet. 2022;54(4):412\u201336.","journal-title":"Nat Genet"},{"issue":"3","key":"1666_CR7","first-page":"401","volume":"10","author":"A Bieger","year":"2023","unstructured":"Bieger A, Rocha A, Bellaver B, Machado L, Da Ros L, Borelli WV, et al. Neuroinflammation biomarkers in the AT(N) framework across the Alzheimer\u2019s disease continuum. J Prev Alzheimers Dis. 2023;10(3):401\u201317.","journal-title":"J Prev Alzheimers Dis"},{"key":"1666_CR8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.nbd.2016.07.007","volume":"107","author":"E Zenaro","year":"2017","unstructured":"Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer\u2019s disease. Neurobiol Dis. 2017;107:41\u201356.","journal-title":"Neurobiol Dis"},{"issue":"5","key":"1666_CR9","doi-asserted-by":"publisher","first-page":"651","DOI":"10.3390\/jcm8050651","volume":"8","author":"K Govindpani","year":"2019","unstructured":"Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, et al. Vascular dysfunction in Alzheimer\u2019s disease: a prelude to the pathological process or a consequence of it? J Clin Med. 2019;8(5):651.","journal-title":"J Clin Med"},{"key":"1666_CR10","doi-asserted-by":"publisher","first-page":"618986","DOI":"10.3389\/fncel.2020.618986","volume":"14","author":"J Steinman","year":"2020","unstructured":"Steinman J, Sun HS, Feng ZP. Microvascular alterations in Alzheimer\u2019s disease. Front Cell Neurosci. 2020;14:618986.","journal-title":"Front Cell Neurosci"},{"issue":"2","key":"1666_CR11","doi-asserted-by":"publisher","first-page":"e12385","DOI":"10.1002\/trc2.12385","volume":"9","author":"J Cummings","year":"2023","unstructured":"Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer\u2019s disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385.","journal-title":"Alzheimers Dement (N Y)"},{"issue":"6","key":"1666_CR12","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1001\/jama.2023.13239","volume":"330","author":"JR Sims","year":"2023","unstructured":"Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512\u201327.","journal-title":"JAMA"},{"issue":"4","key":"1666_CR13","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1007\/s13311-023-01405-0","volume":"20","author":"G Yadollahikhales","year":"2023","unstructured":"Yadollahikhales G, Rojas JC. Anti-amyloid immunotherapies for Alzheimer\u2019s disease: a 2023 clinical update. Neurotherapeutics. 2023;20(4):914\u201331.","journal-title":"Neurotherapeutics"},{"issue":"4","key":"1666_CR14","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1111\/dom.12849","volume":"19","author":"ZZ Htike","year":"2017","unstructured":"Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524\u201336.","journal-title":"Diabetes Obes Metab"},{"key":"1666_CR15","doi-asserted-by":"publisher","first-page":"935823","DOI":"10.3389\/fphar.2022.935823","volume":"13","author":"X Gao","year":"2022","unstructured":"Gao X, Hua X, Wang X, Xu W, Zhang Y, Shi C, et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13:935823.","journal-title":"Front Pharmacol"},{"key":"1666_CR16","doi-asserted-by":"publisher","first-page":"721135","DOI":"10.3389\/fendo.2021.721135","volume":"12","author":"X Zhao","year":"2021","unstructured":"Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, et al. GLP-1 receptor agonists: beyond their pancreatic effects. Front Endocrinol (Lausanne). 2021;12:721135.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"7","key":"1666_CR17","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1038\/s41591-018-0109-4","volume":"24","author":"L Brundin","year":"2018","unstructured":"Brundin L, Bergkvist L, Brundin P. Fire prevention in the Parkinson\u2019s disease brain. Nat Med. 2018;24(7):900\u20132.","journal-title":"Nat Med"},{"issue":"7","key":"1666_CR18","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1002\/oby.23772","volume":"31","author":"C De Barra","year":"2023","unstructured":"De Barra C, Khalil M, Mat A, O\u2019Donnell C, Shaamile F, Brennan K, et al. Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function. Obesity (Silver Spring). 2023;31(7):1787\u201397.","journal-title":"Obes (Silver Spring)"},{"issue":"9","key":"1666_CR19","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/nm919","volume":"9","author":"MJ During","year":"2003","unstructured":"During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9(9):1173\u20139.","journal-title":"Nat Med"},{"issue":"1","key":"1666_CR20","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/s42003-021-02208-9","volume":"4","author":"Z Li","year":"2021","unstructured":"Li Z, Chen X, Vong JSL, Zhao L, Huang J, Yan LYC, et al. Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner. Commun Biol. 2021;4(1):656.","journal-title":"Commun Biol"},{"issue":"1","key":"1666_CR21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s40478-021-01180-z","volume":"9","author":"JS Park","year":"2021","unstructured":"Park JS, Kam TI, Lee S, Park H, Oh Y, Kwon SH, et al. Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer\u2019s disease. Acta Neuropathol Commun. 2021;9(1):78.","journal-title":"Acta Neuropathol Commun"},{"key":"1666_CR22","doi-asserted-by":"crossref","unstructured":"Rode AKO, Buus TB, Mraz V, Al-Jaberi FAH, Lopez DV, Ford SL, et al. Induced human regulatory T cells express the glucagon-like peptide-1 receptor. Cells. 2022;11(16):2587.","DOI":"10.3390\/cells11162587"},{"issue":"7","key":"1666_CR23","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/s41591-018-0051-5","volume":"24","author":"SP Yun","year":"2018","unstructured":"Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson\u2019s disease. Nat Med. 2018;24(7):931\u20138.","journal-title":"Nat Med"},{"issue":"3","key":"1666_CR24","doi-asserted-by":"publisher","first-page":"943","DOI":"10.14336\/AD.2021.1029","volume":"13","author":"Q Zhang","year":"2022","unstructured":"Zhang Q, Liu C, Shi R, Zhou S, Shan H, Deng L, et al. Blocking C3d+\/GFAP+ A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after ischemic stroke. Aging Dis. 2022;13(3):943\u201359.","journal-title":"Aging Dis"},{"issue":"1","key":"1666_CR25","doi-asserted-by":"publisher","first-page":"4413","DOI":"10.1038\/s41467-020-18249-3","volume":"11","author":"L Zhao","year":"2020","unstructured":"Zhao L, Li Z, Vong JSL, Chen X, Lai HM, Yan LYC, et al. Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain. Nat Commun. 2020;11(1):4413.","journal-title":"Nat Commun"},{"issue":"S10","key":"1666_CR26","doi-asserted-by":"publisher","first-page":"e063862","DOI":"10.1002\/alz.063862","volume":"18","author":"MQ Ludwig","year":"2022","unstructured":"Ludwig MQ, Belmont-Rausch DM, Bentsen MA, Secher A, Hansen SAN, Egerod KL, et al. A lipopolysaccharide mouse model mirrors neuroinflammatory transcriptional signatures of human Alzheimer\u2019s disease, and the glucagon-like peptide-1 receptor agonist semaglutide attenuates neuroinflammation in this model. Alzheimers Dement. 2022;18(S10):e063862.","journal-title":"Alzheimers Dement"},{"key":"1666_CR27","doi-asserted-by":"publisher","first-page":"3094642","DOI":"10.1155\/2016\/3094642","volume":"2016","author":"YS Lee","year":"2016","unstructured":"Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm. 2016;2016:3094642.","journal-title":"Mediators Inflamm"},{"issue":"1","key":"1666_CR28","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1186\/s12933-022-01585-7","volume":"21","author":"O Mosenzon","year":"2022","unstructured":"Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol. 2022;21(1):172.","journal-title":"Cardiovasc Diabetol"},{"key":"1666_CR29","doi-asserted-by":"publisher","first-page":"108","DOI":"10.3389\/fnagi.2016.00108","volume":"8","author":"M Gejl","year":"2016","unstructured":"Gejl M, Gjedde A, Egefjord L, M\u00f8ller A, Hansen SB, Vang K, et al. 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. 2016;8:108.","journal-title":"Front Aging Neurosci"},{"issue":"S9","key":"1666_CR30","doi-asserted-by":"publisher","first-page":"e057848","DOI":"10.1002\/alz.057848","volume":"17","author":"P Edison","year":"2021","unstructured":"Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer\u2019s disease. Alzheimers Dement. 2021;17(S9):e057848.","journal-title":"Alzheimers Dement"},{"issue":"S21","key":"1666_CR31","doi-asserted-by":"publisher","first-page":"e080538","DOI":"10.1002\/alz.080538","volume":"19","author":"P Edison","year":"2023","unstructured":"Edison P, Femminella GD, Ritchie C, Nowell J, Holmes C, Walker Z, et al. MRI changes following treatment of GLP-1 analogue, liraglutide in Alzheimer\u2019s disease. Alzheimers Dement. 2023;19(S21):e080538.","journal-title":"Alzheimer\u2019s Dement"},{"issue":"1","key":"1666_CR32","doi-asserted-by":"publisher","first-page":"e12268","DOI":"10.1002\/trc2.12268","volume":"8","author":"CH N\u00f8rgaard","year":"2022","unstructured":"N\u00f8rgaard CH, Friedrich S, Hansen CT, Gerds T, Ballard C, M\u00f8ller DV, et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N Y). 2022;8(1):e12268.","journal-title":"Alzheimers Dement (N Y)"},{"issue":"7","key":"1666_CR33","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/S1474-4422(20)30173-3","volume":"19","author":"T Cukierman-Yaffe","year":"2020","unstructured":"Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, Garc\u00eda-P\u00e9rez LE, Lakshmanan M, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020;19(7):582\u201390.","journal-title":"Lancet Neurol"},{"key":"1666_CR34","doi-asserted-by":"publisher","first-page":"153331751989954","DOI":"10.1177\/1533317519899546","volume":"35","author":"H Akimoto","year":"2020","unstructured":"Akimoto H, Negishi A, Oshima S, Wakiyama H, Okita M, Horii N, et al. Antidiabetic drugs for the risk of Alzheimer disease in patients with type 2 DM using FAERS. Am J Alzheimers Dis Other Demen. 2020;35:1533317519899546.","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"5","key":"1666_CR35","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1530\/EJE-19-0259","volume":"181","author":"IK Wium-Andersen","year":"2019","unstructured":"Wium-Andersen IK, Osler M, J\u00f8rgensen MB, Rungby J, Wium-Andersen MK. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case-control study. Eur J Endocrinol. 2019;181(5):499\u2013507.","journal-title":"Eur J Endocrinol"},{"issue":"Suppl 1","key":"1666_CR36","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.2337\/db23-1802-PUB","volume":"72","author":"T Wang","year":"2023","unstructured":"Wang T, Buse JB, Pate V, St\u00fcrmer T. 1802-PUB: Liraglutide as a potential drug repurposing candidate for Alzheimer\u2019s disease and related dementia\u2014real-world evidence. Diabetes. 2023;72(Suppl 1):1802\u2013PUB.","journal-title":"Diabetes"},{"key":"1666_CR37","doi-asserted-by":"crossref","unstructured":"Wang W, Wang Q, Qi X, Gurney M, Perry G, Volkow ND, et al. Associations of semaglutide with first-time diagnosis of Alzheimer\u2019s disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimer\u2019s & Dementia. 2024;20(12):8661\u201372.","DOI":"10.1002\/alz.14313"},{"key":"1666_CR38","unstructured":"FDA. RYBELSUS prescribing information. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/213051s000lbl.pdf. Accessed 3 January 2025."},{"key":"1666_CR39","unstructured":"FDA. OZEMPIC prescribing information. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/209637lbl.pdf. Accessed 3 January 2025."},{"key":"1666_CR40","unstructured":"FDA. WEGOVY prescribing information. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/215256s000lbl.pdf. Accessed 3 January 2025."},{"key":"1666_CR41","doi-asserted-by":"publisher","first-page":"101737","DOI":"10.1016\/j.eclinm.2022.101737","volume":"55","author":"S Verma","year":"2023","unstructured":"Verma S, Bhatta M, Davies M, Deanfield JE, Garvey WT, Jensen C, et al. Effects of once-weekly semaglutide 2.4\u00a0mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials. EClinicalMedicine. 2023;55:101737.","journal-title":"EClinicalMedicine"},{"issue":"3","key":"1666_CR42","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/dom.13955","volume":"22","author":"M Husain","year":"2020","unstructured":"Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020;22(3):442\u201351.","journal-title":"Diabetes Obes Metab"},{"issue":"19","key":"1666_CR43","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","volume":"375","author":"SP Marso","year":"2016","unstructured":"Marso SP, Bain SC, Consoli A, Eliaschewitz FG, J\u00f3dar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834\u201344.","journal-title":"N Engl J Med"},{"issue":"9","key":"1666_CR44","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1056\/NEJMoa1901118","volume":"381","author":"M Husain","year":"2019","unstructured":"Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841\u201351.","journal-title":"N Engl J Med"},{"issue":"9","key":"1666_CR45","doi-asserted-by":"publisher","first-page":"2749","DOI":"10.1161\/STROKEAHA.121.037775","volume":"53","author":"WD Strain","year":"2022","unstructured":"Strain WD, Frenkel O, James MA, Leiter LA, Rasmussen S, Rothwell PM, et al. Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomized SUSTAIN 6 and PIONEER 6. Stroke. 2022;53(9):2749\u201357.","journal-title":"Stroke"},{"issue":"5","key":"1666_CR46","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1002\/jnr.10611","volume":"72","author":"T Perry","year":"2003","unstructured":"Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003;72(5):603\u201312.","journal-title":"J Neurosci Res"},{"key":"1666_CR47","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.3389\/fnins.2019.01112","volume":"13","author":"M Grieco","year":"2019","unstructured":"Grieco M, Giorgi A, Gentile MC, d\u2019Erme M, Morano S, Maras B, et al. Glucagon-like peptide-1: a focus on neurodegenerative diseases. Front Neurosci. 2019;13:1112.","journal-title":"Front Neurosci"},{"issue":"4","key":"1666_CR48","doi-asserted-by":"publisher","first-page":"877","DOI":"10.3233\/JAD-143090","volume":"46","author":"HH Hansen","year":"2015","unstructured":"Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, et al. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer\u2019s disease. J Alzheimers Dis. 2015;46(4):877\u201388.","journal-title":"J Alzheimers Dis"},{"key":"1666_CR49","doi-asserted-by":"publisher","first-page":"114187","DOI":"10.1016\/j.bcp.2020.114187","volume":"180","author":"TS Salameh","year":"2020","unstructured":"Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer\u2019s and Parkinson\u2019s disease therapeutics. Biochem Pharmacol. 2020;180:114187.","journal-title":"Biochem Pharmacol"},{"key":"1666_CR50","doi-asserted-by":"crossref","unstructured":"Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-R\u00f8nne J, Alanentalo T, Baquero AF, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5(6):e133429.","DOI":"10.1172\/jci.insight.133429"},{"key":"1666_CR51","doi-asserted-by":"publisher","first-page":"101102","DOI":"10.1016\/j.molmet.2020.101102","volume":"46","author":"MA Nauck","year":"2021","unstructured":"Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102.","journal-title":"Mol Metab"},{"issue":"4","key":"1666_CR52","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack Jr","year":"2018","unstructured":"Jack CR Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement. 2018;14(4):535\u201362.","journal-title":"Alzheimers Dement"},{"issue":"7","key":"1666_CR53","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1212\/WNL.0b013e31820ce6a5","volume":"76","author":"YL Chang","year":"2011","unstructured":"Chang YL, Bondi MW, McEvoy LK, Fennema-Notestine C, Salmon DP, Galasko D, et al. Global clinical dementia rating of 0.5 in MCI masks variability related to level of function. Neurology. 2011;76(7):652\u20139.","journal-title":"Neurology"},{"key":"1666_CR54","unstructured":"FDA. Guidance for Industry: Clinical Trial Imaging Endpoint Process Standards. 2018."},{"issue":"6","key":"1666_CR55","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1161\/01.STR.32.6.1318","volume":"32","author":"LO Wahlund","year":"2001","unstructured":"Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sj\u00f6gren M, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001;32(6):1318\u201322.","journal-title":"Stroke"},{"issue":"11","key":"1666_CR56","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.1212\/WNL.43.11.2412-a","volume":"43","author":"JC Morris","year":"1993","unstructured":"Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412\u20134.","journal-title":"Neurology"},{"issue":"8","key":"1666_CR57","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1111\/dom.14054","volume":"22","author":"TK Thethi","year":"2020","unstructured":"Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: the PIONEER programme. Diabetes Obes Metab. 2020;22(8):1263\u201377.","journal-title":"Diabetes Obes Metab"},{"issue":"24","key":"1666_CR58","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","volume":"389","author":"AM Lincoff","year":"2023","unstructured":"Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221\u201332.","journal-title":"N Engl J Med"},{"issue":"12","key":"1666_CR59","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","volume":"389","author":"MN Kosiborod","year":"2023","unstructured":"Kosiborod MN, Abildstr\u00f8m SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069\u201384.","journal-title":"N Engl J Med"},{"key":"1666_CR60","doi-asserted-by":"publisher","first-page":"996179","DOI":"10.3389\/fpubh.2022.996179","volume":"10","author":"Y Shu","year":"2022","unstructured":"Shu Y, He X, Wu P, Liu Y, Ding Y, Zhang Q. Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system. Front Public Health. 2022;10:996179.","journal-title":"Front Public Health"},{"issue":"5","key":"1666_CR61","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1007\/s11154-022-09735-8","volume":"23","author":"VR Aroda","year":"2022","unstructured":"Aroda VR, Blonde L, Pratley RE. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Rev Endocr Metab Disord. 2022;23(5):979\u201394.","journal-title":"Rev Endocr Metab Disord"},{"issue":"18","key":"1666_CR62","doi-asserted-by":"publisher","first-page":"7370","DOI":"10.1021\/acs.jmedchem.5b00726","volume":"58","author":"J Lau","year":"2015","unstructured":"Lau J, Bloch P, Sch\u00e4ffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370\u201380.","journal-title":"J Med Chem"},{"issue":"S21","key":"1666_CR63","doi-asserted-by":"publisher","first-page":"e076540","DOI":"10.1002\/alz.076540","volume":"19","author":"M Sabbagh","year":"2023","unstructured":"Sabbagh M, Boschini C, Cohen S, Fugger M, Jessen F, Martino GG, et al. Safety profile of semaglutide in people aged 55 years and over: pooled data from the PIONEER, SUSTAIN and STEP phase 3 clinical programmes. Alzheimers Dement. 2023;19(S21):e076540.","journal-title":"Alzheimer\u2019s Dement"},{"key":"1666_CR64","doi-asserted-by":"publisher","first-page":"645617","DOI":"10.3389\/fendo.2021.645617","volume":"12","author":"JJ Meier","year":"2021","unstructured":"Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol (Lausanne). 2021;12:645617.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"6","key":"1666_CR65","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s40266-017-0462-x","volume":"34","author":"BAA Franx","year":"2017","unstructured":"Franx BAA, Arnoldussen IAC, Kiliaan AJ, Gustafson DR. Weight loss in patients with dementia: considering the potential impact of pharmacotherapy. Drugs Aging. 2017;34(6):425\u201336.","journal-title":"Drugs Aging"},{"issue":"Suppl 1","key":"1666_CR66","first-page":"S92","volume":"10","author":"P Scheltens","year":"2023","unstructured":"Scheltens P, Atri A, Feldman H, Hansson O, Knop F, Sano M, et al. Baseline characteristics from evoke and evoke+: two phase 3 randomized placebo-controlled trials of oral semaglutide in patients with early Alzheimer\u2019s disease. J Prev Alzheimers Dis. 2023;10(Suppl 1):S92\u20133. Poster LP018; Presented at CTAD 2023.","journal-title":"J Prev Alzheimers Dis"},{"issue":"3","key":"1666_CR67","first-page":"388","volume":"9","author":"R Raman","year":"2022","unstructured":"Raman R, Aisen PS, Carillo MC, Detke M, Grill JD, Okonkwo OC, et al. Tackling a major deficiency of diversity in Alzheimer\u2019s disease therapeutic trials: an CTAD Task Force report. J Prev Alzheimers Dis. 2022;9(3):388\u201392.","journal-title":"J Prev Alzheimers Dis"},{"key":"1666_CR68","doi-asserted-by":"publisher","first-page":"927","DOI":"10.3389\/fneur.2020.00927","volume":"11","author":"HW Kim","year":"2020","unstructured":"Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer\u2019s disease: a review. Front Neurol. 2020;11:927.","journal-title":"Front Neurol"},{"issue":"1","key":"1666_CR69","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13195-022-00984-y","volume":"14","author":"SS Assun\u00e7\u00e3o","year":"2022","unstructured":"Assun\u00e7\u00e3o SS, Sperling RA, Ritchie C, Kerwin DR, Aisen PS, Lansdall C, et al. Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer\u2019s disease. Alzheimers Res Ther. 2022;14(1):54.","journal-title":"Alzheimers Res Ther"},{"issue":"3","key":"1666_CR70","first-page":"507","volume":"9","author":"S Cohen","year":"2022","unstructured":"Cohen S, Cummings J, Knox S, Potashman M, Harrison J. Clinical trial endpoints and their clinical meaningfulness in early stages of Alzheimer\u2019s disease. J Prev Alzheimers Dis. 2022;9(3):507\u201322.","journal-title":"J Prev Alzheimers Dis"},{"issue":"3","key":"1666_CR71","first-page":"595","volume":"10","author":"SP Dickson","year":"2023","unstructured":"Dickson SP, Wessels AM, Dowsett SA, Mallinckrodt C, Sparks JD, Chatterjee S, et al. \u2018Time saved\u2019 as a demonstration of clinical meaningfulness and illustrated using the donanemab TRAILBLAZER-ALZ study findings. J Prev Alzheimers Dis. 2023;10(3):595\u20139.","journal-title":"J Prev Alzheimers Dis"},{"issue":"22","key":"1666_CR72","doi-asserted-by":"publisher","first-page":"4757","DOI":"10.1016\/j.cell.2023.09.023","volume":"186","author":"AL Boxer","year":"2023","unstructured":"Boxer AL, Sperling R. Accelerating Alzheimer\u2019s therapeutic development: the past and future of clinical trials. Cell. 2023;186(22):4757\u201372.","journal-title":"Cell"},{"key":"1666_CR73","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/978-3-030-05542-4_2","volume":"1118","author":"J Cummings","year":"2019","unstructured":"Cummings J. The role of biomarkers in Alzheimer\u2019s disease drug development. Adv Exp Med Biol. 2019;1118:29\u201361.","journal-title":"Adv Exp Med Biol"}],"container-title":["Alzheimer's Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-024-01666-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13195-024-01666-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-024-01666-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T15:02:24Z","timestamp":1736348544000},"score":1,"resource":{"primary":{"URL":"https:\/\/alzres.biomedcentral.com\/articles\/10.1186\/s13195-024-01666-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,8]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1666"],"URL":"https:\/\/doi.org\/10.1186\/s13195-024-01666-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-5043179\/v1","asserted-by":"object"}]},"ISSN":["1758-9193"],"issn-type":[{"value":"1758-9193","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,8]]},"assertion":[{"value":"6 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The evoke and evoke+\u2009trials are being conducted in accordance with the consensus ethical principles derived from international guidelines including the Declaration of Helsinki and applicable ICH Good Clinical Practice (GCP) Guideline, as well as local laws and regulations. The trials were approved by local ethics committees and institutional review boards (listed in Additional file 1 in Supplementary Information). All participants and study partners provided written informed consent to participate in the trials.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"JC: provided consultation to Acadia, Actinogen, Acumen, Alpha Cognition, Aprinoia, AriBio, Artery, Biogen, BioVie, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GemVax, Genentech, GAP Innovations, Janssen, Jocasta, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, PRODEO, Prothena, reMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren Therapeutics. AA: has received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer\u2019s Association, Axovant, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Novo Nordisk, ONO, Prothena, Qynapse, Roche\/Genentech, Sunovion, Suven, and Synexus. AA receives book royalties from Oxford University Press for a medical book on dementia. AA receives institutional research grant\/contract funding from National Institute on Aging\/National Institutes of Health (1P30AG072980), NIA\/NIH U24AG057437, AZ DHS (CTR040636), Foundation for NIH (FNIH), Washington University in St. Louis, and Gates Ventures. AA\u2019s institution receives\/received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves\/served as contracted site principal investigator. AA has received\/receives honoraria from Novo Nordisk for consulting activities including for service on the evoke\/evoke+ program Steering Committee. HHF: reports grants to the University of California San Diego (UCSD) from LuMind Foundation, Annovis (QR Pharma), AC Immune, Biohaven Pharmaceuticals, and Vivoryon (Probiodrug). He also reports service agreements through UCSD for consulting with Arrowhead Pharmaceuticals, Axon Neuroscience, LuMind Foundation, and Novo Nordisk. He reports serving on a data monitoring committee and data and safety monitoring board for Janssen Research & Development LLC and Roche\/Genentech Pharmaceuticals with service agreements through UCSD, as well as serving on the Scientific Advisory Board for the Tau Consortium. He reports travel expenses through UCSD from Novo Nordisk and Royal Society of Canada. He receives personal funds for Detecting and Treating Dementia Serial Number 12\/3- 2691 U.S. Patent No. PCT\/US2007\/07008, Washington DC, U.S. Patent and Trademark Office. He also received philanthropic support for Alzheimer\u2019s therapeutic research through the Epstein Family Alzheimer\u2019s Research Collaboration.\u00a0OH: acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eisai, Eli Lilly, Fujirebio, GE Healthcare, Pfizer, and Roche; and received consultancy\/speaker fees from AC Immune, ALZpath, Amylyx, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche, and Siemens.\u00a0FKK: has served on scientific advisory panels and\/or been part of speaker\u2019s bureaus for, served as a consultant to, and\/or received research support from 89bio, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD\/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; is a co-founder of and minority shareholder in Antag Therapeutics, and owns shares in Eli Lilly, Novo Nordisk, and Zealand Pharma; is an employee of Novo Nordisk A\/S. MS: has served as a scientific advisory board member for Medivation and as a consultant for Bayer Schering Pharma, Bristol Myers Squibb, Elan, Genentech, Janssen, Medivation, Medpace, Otsuka, Pfizer, Takeda, and United BioSource.\u00a0PJ: is an employee of Novo Nordisk A\/S. TL: is an employee of Novo Nordisk A\/S.\u00a0PS: is a full-time employee of EQT Life Sciences (formerly LSP). He reports having received consultancy fees (paid to Vrije Universiteit Amsterdam) from AC Immune, Alzheon, BrainStorm Cell, FUJIFILM\/Toyama, Green Valley, and Novo Nordisk.\u00a0No remuneration was received by any author for the development of this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14"}}