{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:23:57Z","timestamp":1787822637084,"version":"build-2784847793"},"reference-count":75,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,8,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Although Alzheimer's disease (AD) carries the highest clinical trial failure rate of any major therapeutic area, the strategic lessons from more than two decades of negative outcomes remain insufficiently integrated into drug development practice. To date, trial failures have been examined largely in isolation, with limited attention to the recurring patterns that may connect them across therapeutic classes and disease stages. In this perspective, we propose a taxonomy that assigns AD therapeutic failures to five categories according to the primary driver of each negative outcome\u2014namely wrong target, wrong timing, wrong patient, insufficient target engagement, and wrong endpoint. We subsequently applied this framework to a representative set of drugs that entered clinical testing between 2000 and 2025, comprising anti\u2010amyloid monoclonal antibodies, \u03b2\u2010site amyloid precursor protein\u2010cleaving enzyme 1 inhibitors, tau\u2010directed immunotherapies, neuroimmune\u2010targeting agents, and metabolic repurposing candidates. Analysis across classes showed that the distribution of failure categories shifted progressively over time, from predominantly target\u2010related failures in the mid\u2010to\u2010late 2010s toward patient\u2010selection and endpoint\u2010related failures in the current decade. From these patterns, we formulated strategic recommendations for next\u2010generation trial design\u2014including biomarker\u2010driven patient enrichment, mechanism\u2010specific endpoint validation, and adaptive platform architectures. Because numerous failures examined here replicate the negative outcomes of earlier programs, we conclude that a substantial proportion of late\u2010stage AD trial failures may be structurally predictable and, through systematic classification, at least in part preventable. Despite these promising findings, the proposed taxonomy should be considered a working heuristic requiring external calibration before prospective deployment.<\/jats:p>","DOI":"10.1096\/fj.202601680rr","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:05:15Z","timestamp":1787216715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anatomy of a Setback: A Taxonomy of Clinical Trial Failures in Alzheimer's Disease and Strategic Lessons for the Future"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3908-0290","authenticated-orcid":false,"given":"Enzo","family":"Emanuele","sequence":"first","affiliation":[{"name":"2E Science  Robbio Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6512-611X","authenticated-orcid":false,"given":"Piercarlo","family":"Minoretti","sequence":"additional","affiliation":[{"name":"Department of Social Sciences Miguel de Cervantes European University (UEMC)  Valladolid Spain"},{"name":"Studio Minoretti  Oggiono Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010020\u20100687\u20106"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.00265"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753\u2010022\u201001721\u20101"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102713"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242216288"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adv8269"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010019\u201002036\u20106"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1352822"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.13009"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010022\u201000714\u2010w"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22042022"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/neurolint18020037"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010025\u201000872\u20107"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt269"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2025.2546868"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010023\u201001851\u20102"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010021\u201001569\u2010z"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304430"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(25)00024\u20109"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.3988"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010020\u201000614\u20105"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.1375"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000208061"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR\u2010230012"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010023\u201001169\u2010x"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010025\u201000828\u2010x"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1177\/1179573520907397"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12465"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213954"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1590\/1980\u20105764\u2010DN\u20102025\u2010E001"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70113"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.4857"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1312889"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305032"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207663"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.044910"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.069287"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(16)31275\u20102"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD\u2010230899"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010025\u201001911\u20103"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12883\u2010024\u201003596\u20101"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1039\/d5md01095k"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11030\u2010026\u201011546\u2010x"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27248823"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010023\u201000523\u2010w"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001455\u2010x"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad024"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010021\u201001369\u20108"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2025.e00811"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70217"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100204"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.5582\/bst.2023.01288"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1039\/d5ra03578c"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425247.2025.2462767"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.41"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12959"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2020.00457"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000073623.84147.a8"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(08)61075\u20102"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1304839"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad188"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010024\u201002709\u2010z"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105322"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13164661"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113337"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12010"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1210974"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2021.21"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100230"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.07.005"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics16010155"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601680RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202601680RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202601680RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:14:50Z","timestamp":1787822090000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202601680RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":75,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2026,8,31]]}},"alternative-id":["10.1096\/fj.202601680RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202601680rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"assertion":[{"value":"2026-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72221"}}