{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:50:22Z","timestamp":1789023022059,"version":"build-2803163510"},"reference-count":264,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-\u03b2 (A\u03b2) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-A\u03b2 antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood\u2013brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.<\/jats:p>","DOI":"10.3389\/fcell.2026.1766762","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T05:20:32Z","timestamp":1775712032000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer\u2019s disease therapy"],"prefix":"10.3389","volume":"14","author":[{"given":"Alberto","family":"Ouro","sequence":"first","affiliation":[{"name":"NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)","place":["Santiago de Compostela, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel A.","family":"Ben-Dor","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]},{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Debasa-Mouce","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly","family":"Gulkarov","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"De Leon","sequence":"additional","affiliation":[{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Castro-Mosquera","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Sobrino","sequence":"additional","affiliation":[{"name":"NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)","place":["Santiago de Compostela, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Bougea","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Medical School National and Kapodistrian University of Athens","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison B.","family":"Reiss","sequence":"additional","affiliation":[{"name":"Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]},{"name":"Department of Medicine, NYU Grossman Long Island School of Medicine","place":["Mineola, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3513","DOI":"10.1093\/brain\/awae216","article-title":"Increases in Amyloid-\u039242 slow cognitive and clinical decline in Alzheimer\u2019s disease trials","volume":"147","author":"Abanto","year":"2024","journal-title":"Brain"},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/TRC2.12498","article-title":"APOLLOE4 phase 3 study of oral ALZ-801\/Valiltramiprosate in APOE \u03954\/\u03954 homozygotes with early Alzheimer\u2019s disease: trial design and baseline characteristics","volume":"10","author":"Abushakra","year":"2024","journal-title":"Alzheimers Dement. 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