{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T02:44:35Z","timestamp":1782182675338,"version":"3.54.5"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T00:00:00Z","timestamp":1699228800000},"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. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>This meta-analysis evaluates the efficacy and safety of amyloid-\u03b2 (A\u03b2) targeted therapies for delaying cognitive deterioration in Alzheimer\u2019s disease (AD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PubMed, EMBASE, the Cochrane Library, and <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link> were systematically searched to identify relevant studies published before January 18, 2023.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We pooled 33,689 participants from 42 studies. The meta-analysis showed no difference between anti-A\u03b2 drugs and placebo in the Alzheimer\u2019s Disease Assessment Scale\u2013Cognitive Subscale (ADAS-Cog), and anti-A\u03b2 drugs were associated with a high risk of adverse events [ADAS-Cog: MDs\u2009=\u2009\u22120.08 (\u22120.32 to 0.15), <jats:italic>p<\/jats:italic> =\u20090.4785; AEs: RR\u2009=\u20091.07 (1.02 to 1.11), <jats:italic>p<\/jats:italic> =\u20090.0014]. Monoclonal antibodies outperformed the placebo in delaying cognitive deterioration as measured by ADAS-Cog, Clinical Dementia Rating\u2013Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE) and Alzheimer\u2019s Disease Cooperative Study\u2013Activities of Daily Living (ADCS-ADL), without increasing the risk of adverse events [ADAS-Cog: MDs\u2009=\u2009\u22120.55 (\u22120.89 to 0.21), <jats:italic>p<\/jats:italic> =\u20090.001; CDR-SB: MDs\u2009=\u2009\u22120.19 (\u22120.29 to \u22120.10), <jats:italic>p<\/jats:italic> &amp;lt;\u20090.0001; MMSE: MDs\u2009=\u20090.19 (0.00 to 0.39), <jats:italic>p<\/jats:italic> =\u20090.05; ADCS-ADL: MDs\u2009=\u20091.26 (0.84 to 1.68), <jats:italic>p<\/jats:italic> &amp;lt;\u20090.00001]. Intravenous immunoglobulin and \u03b3-secretase modulators (GSM) increased cognitive decline in CDR-SB [MDs\u2009=\u20090.45 (0.17 to 0.74), <jats:italic>p<\/jats:italic> =\u20090.002], but had acceptable safety profiles in AD patients. \u03b3-secretase inhibitors (GSI) increased cognitive decline in ADAS-Cog, and also in MMSE and ADCS-ADL. BACE-1 inhibitors aggravated cognitive deterioration in the outcome of the Neuropsychiatric Inventory (NPI). GSI and BACE-1 inhibitors caused safety concerns. No evidence indicates active A\u03b2 immunotherapy, MPAC, or tramiprosate have effects on cognitive function and tramiprosate is associated with serious adverse events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Current evidence does not show that anti-A\u03b2 drugs have an effect on cognitive performance in AD patients. However, monoclonal antibodies can delay cognitive decline in AD. Development of other types of anti-A\u03b2 drugs should be cautious.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic Review Registration<\/jats:title><jats:p>PROSPERO (<jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>), identifier CRD42023391596.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1257973","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T10:07:43Z","timestamp":1699265263000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["The efficacy and safety of anti-A\u03b2 agents for delaying cognitive decline in Alzheimer\u2019s disease: a meta-analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Jiaxuan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruisi","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouqing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/nature.2016.21045","article-title":"Leading Alzheimer\u2019s theory survives drug failure","volume":"540","author":"Abbott","year":"2016","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1056\/NEJMp2110468","article-title":"Revisiting FDA approval of Aducanumab","volume":"385","author":"Alexander","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jalz.2019.01.010","article-title":"2019 Alzheimer's disease facts and figures","volume":"15","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"20210405","DOI":"10.1016\/j.arr.2021.101339","article-title":"Effects of monoclonal antibodies against amyloid-\u03b2 on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of phase III RCTs in Alzheimer's disease","volume":"68","author":"Avgerinos","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/nrm.2016.94","article-title":"Notch signalling in context","volume":"17","author":"Bray","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41593-018-0289-8","article-title":"Tau impairs neural circuits, dominating amyloid-\u03b2 effects, in Alzheimer models in vivo","volume":"22","author":"Busche","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3197","DOI":"10.1021\/bi400377p","article-title":"Development and mechanism of \u03b3-secretase modulators for Alzheimer's disease","volume":"52","author":"Crump","year":"2013","journal-title":"Biochemistry"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e12179","DOI":"10.1002\/trc2.12179","article-title":"Alzheimer's disease drug development pipeline: 2021","volume":"7","author":"Cummings","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1126\/scitranslmed.aag0481","article-title":"Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy","volume":"9","author":"DeVos","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1706441","article-title":"Randomized trial of Verubecestat for mild-to-moderate Alzheimer\u2019s disease","volume":"378","author":"Egan","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"E53-E65","DOI":"10.25011\/cim.v42i1.32393","article-title":"Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer's disease: a systematic review and network meta-analysis","volume":"42","author":"Foroutan","year":"2019","journal-title":"Clin. Invest. Med."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"a006270","DOI":"10.1101\/cshperspect.a006270","article-title":"Trafficking and proteolytic processing of APP","volume":"2","author":"Haass","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"645","DOI":"10.3233\/jad-160907","article-title":"Recent Progress in Alzheimer's disease research, part 3: diagnosis and treatment","volume":"57","author":"Hane","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/nm.4443","article-title":"Amyloid-\u03b2 plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation","volume":"24","author":"He","year":"2018","journal-title":"Nat. Med."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s40265-023-01851-2","article-title":"Lecanemab: first approval","volume":"83","author":"Hoy","year":"2023","journal-title":"Drugs"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s12276-022-00754-8","article-title":"\u03b3-Secretase in Alzheimer's disease","volume":"54","author":"Hur","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer's disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3389\/fnins.2018.00025","article-title":"Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer's disease","volume":"12","author":"Kametani","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41573-022-00391-w","article-title":"The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics","volume":"21","author":"Karran","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1212\/wnl.0000000000012452","article-title":"Prescribing Aducanumab in the face of meager efficacy and real risks","volume":"97","author":"Knopman","year":"2021","journal-title":"Neurology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3233\/jad-220046","article-title":"Safety and efficacy of monoclonal antibodies for Alzheimer's disease: a systematic review and Meta-analysis of published and unpublished clinical trials","volume":"87","author":"Lacorte","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/joim.12168","article-title":"Amyloid-\u00df-directed immunotherapy for Alzheimer's disease","volume":"275","author":"Lannfelt","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1001\/jama.2022.24490","article-title":"Lecanemab gains FDA approval for early Alzheimer disease","volume":"329","author":"Larkin","year":"2023","journal-title":"JAMA"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"b2700","DOI":"10.1136\/bmj.b2700","article-title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration","volume":"339","author":"Liberati","year":"2009","journal-title":"BMJ"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1016\/j.ejso.2018.07.052","article-title":"Clinical significance of plasma D-dimer and fibrinogen in digestive cancer: a systematic review and meta-analysis","volume":"44","author":"Lin","year":"2018","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1080\/14737175.2019.1620106","article-title":"Intravenous immunoglobulins for Alzheimer\u2019s disease and mild cognitive impairment due to Alzheimer\u2019s disease: a systematic review with meta-analysis","volume":"19","author":"Liu","year":"2019","journal-title":"Expert. Rev. Neurother."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: an update on pathobiology and treatment strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cells"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1136\/jnnp-2020-323497","article-title":"Anti-A\u03b2 agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis","volume":"91","author":"Lu","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e214495","DOI":"10.1001\/jamahealthforum.2021.4495","article-title":"Estimated annual spending on Aducanumab in the US Medicare program","volume":"3","author":"Mafi","year":"2022","journal-title":"JAMA Health Forum"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/S1474-4422(22)00529-4","article-title":"Lecanemab slows Alzheimer's disease: hope and challenges","volume":"22","author":"Mead","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1523\/jneurosci.4264-11.2012","article-title":"Differential effects between \u03b3-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice","volume":"32","author":"Mitani","year":"2012","journal-title":"J. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1002\/acn3.469","article-title":"Efficacy and safety of anti-amyloid-\u03b2 immunotherapy for Alzheimer's disease: a systematic review and network meta-analysis. Annals of clinical and translational","volume":"4","author":"Mo","year":"2017","journal-title":"Neurology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1002\/med.21622","article-title":"BACE1 inhibitors: current status and future directions in treating Alzheimer's disease","volume":"40","author":"Moussa-Pacha","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1111\/j.1755-5949.2010.00164.x","article-title":"REVIEW: \u03b3-secretase inhibitors for the treatment of Alzheimer's disease: the current state","volume":"16","author":"Panza","year":"2010","journal-title":"CNS Neurosci. Ther."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"14 20220524","DOI":"10.3390\/pharmaceutics14061117","article-title":"Therapeutic approach to Alzheimer's disease: current treatments and new perspectives","volume":"14","author":"Pardo-Moreno","year":"2022","journal-title":"Pharmaceutics"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.3390\/molecules22101692","article-title":"\u03b2-Amyloid and the Pathomechanisms of Alzheimer's disease: a comprehensive view","volume":"22","author":"Penke","year":"2017","journal-title":"Molecules"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s11481-016-9722-5","article-title":"Safety and efficacy of anti-amyloid-\u03b2 immunotherapy in Alzheimer's disease: a systematic review and Meta-analysis","volume":"12","author":"Penninkilampi","year":"2017","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref40","first-page":"267","article-title":"Chapter 16- lessons from antiamyloid-\u03b2 immunotherapies in Alzheimer's disease","volume-title":"Handbook of clinical neurology","author":"Plascencia-Villa","year":"2023"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/jrsm.38","article-title":"Review: Cochrane handbook for systematic reviews for interventions, version 5.1.0, published 3\/2011. Julian P.T. Higgins and Sally green, editors","volume":"2","author":"Shuster","year":"2011","journal-title":"Res. Synth. Methods"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.neuron.2014.10.038","article-title":"The evolution of preclinical Alzheimer\u2019s disease: implications for prevention trials","volume":"84","author":"Sperling","year":"2014","journal-title":"Neuron"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41583-019-0240-3","article-title":"Amyloid-\u03b2-independent regulators of tau pathology in Alzheimer disease","volume":"21","author":"van der Kant","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1007\/s13311-023-01405-0","article-title":"Anti-amyloid immunotherapies for Alzheimer's disease: a 2023 clinical update","volume":"20","author":"Yadollahikhales","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cell.2020.11.049","article-title":"Structural basis of \u03b3-secretase inhibition and modulation by small molecule drugs","volume":"184","author":"Yang","year":"2021","journal-title":"Cells"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"803","DOI":"10.3233\/jad-210225","article-title":"The burden of Alzheimer's disease mortality in the United States, 1999-2018","volume":"82","author":"Zhao","year":"2021","journal-title":"J. Alzheimers Dis."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1257973\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T10:07:47Z","timestamp":1699265267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1257973\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,6]]},"references-count":46,"alternative-id":["10.3389\/fnagi.2023.1257973"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2023.1257973","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,6]]},"article-number":"1257973"}}