Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Jun;12(6):100163.
doi: 10.1016/j.tjpad.2025.100163. Epub 2025 Apr 18.

Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force

D Angioni  1 , L Middleton  2 , R Bateman  3 , P Aisen  4 , A Boxer  5 , S Sha  6 , J Zhou  7 , I Gerlach  8 , R Raman  9 , H Fillit  10 , S Salloway  11 , R Sperling  12 , B Vellas  1 , J Cummings  13
Affiliations
Review

Challenges and opportunities for novel combination therapies in Alzheimer's disease: a report from the EU/US CTAD Task Force

D Angioni et al. J Prev Alzheimers Dis. 2025 Jun.

Abstract

Following the recent approvals of anti-amyloid immunotherapies as "first-in-kind" disease-modifying agents for Alzheimer's disease (AD), there is an emerging emphasis in combination therapies, given the complex and multifactorial etiopathogenesis and pathophysiology of the disease. The EU/US CTAD Task Force met in Madrid in October 2024, to discuss biological rationale and methodological issues and outline potential directions for future research in combination therapies. The Task Force agreed on the necessity and urgency of advancing combination therapies for AD treatment. As of January 1, 2024, in the drug development pipeline, there were 21 combination trials (13 % of all trials). The combination of anti-amyloid and anti-tau therapies could become a central focus of the field. Combinations involving anti-inflammatory and immune mechanisms with anti-amyloid or other therapies also have promise. To facilitate the development and implementation of combination therapies, collaborations between sponsors and public-private partnerships are essential. Optimizing the likelihood of success primarily requires leveraging the use of biomarkers and a clearer understanding of the biological mechanisms underpinning AD and their interactions, especially those involving amyloid, tau, and inflammation, that lead to cognitive decline and progression.

Keywords: Amyloid; Clinical trials; Combination; Tau.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. D.A is an investigator in clinical trials sponsored by Alector, Alzheon, Acadia, Aribio, Biogen, Eisai, Genentech, GSK, Green Valley, Hoffmann-La Roche, Janssen, Medesis Pharma, Nestlé, Novo Nordisk, Otsuka, Regenlife, UCB Pharma. He received consulting fees from Novo Nordisk and lecture fees from Eisai. L.M has received research funding from Johnson & Johnson, Merck, Takeda, Eisai, Gates Ventures, the Davos Alzheimer's Collaborative, UKRI and ADDF, all to Institution. R.B has received research support from the National Institutes of Health, the National Institute on Aging, Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium, Biogen, Eisai, Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, and Janssen. He has also received funding from Eisai, Avid Radiopharmaceuticals, Janssen, Cogstate, Cerveau, and Signant Health, AbbVie, Bristol Myers Squibb, and Novartis. RJB co-founded C2N Diagnostics, which offers the PrecivityAD2 blood test. Washington University and RJB have equity ownership interest in C2N Diagnostics and receive income based on technology and receives income from C2N Diagnostics for serving on the scientific advisory board. He has served as an unpaid member of advisory boards for Roche and Biogen. P.A. has a research collaboration with Eisai and consults with Lilly, Merck, Roche, Genentech, Abbvie, Biogen, ImmunoBrain Checkpoint, AltPep, Alector, Arrowhead and Neurimmune. A.B has served as a paid consultant to Alector, Alexion, Arrowhead, Arvinas, Eli Lilly, Merck, Neurocrine, Ono, Oscotec, Switch and Transposon. Institution received research support from Biogen and Eisai for serving as a site investigator for clinical trials, as well as from Regeneron. S.S. served as consultant and/or Advisor for Cognition Therapeutics, Eisai Inc, Guidepoint global, Expert Connect; and received Grant/Research Support from: Aribio, Biogen, Cognition Therapeutics, Eisai Inc., Eli Lilly, Janssen. J. Z., is a fully time employee of Eisai Inc. I. G. is a full time employee and stockholder of F. Hoffmann-La Roche. R.R. has received research support from Eli Lilly and Eisai as part of public-private partnership grant, all to the Institution. S.Sa. reports grants and personal fees from Lilly, Roche, Biogen, Genentech, Eisai, Acumen; personal fees from NovoNordisk, Neurophet, Acumen, Prothena, LabCorp, Abbvie, outside the submitted work. He is an Associate Editor of the Journal of Prevention of Alzheimer's and of Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. H. F. reports personal fees from Alector, Promis, outside the submitted work. R.S. reports personal fees from Abbvie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Genentech, Janssen, Nervgen, Oligomerix, Prothena, Roche, Vigil Neuroscience, Ionis, Vaxxinity, grants and other from Alzheimer's Association, grants from National Institute on Aging, GHR Foundation, Eli Lilly, Eisai, other from Clinical Trials in Alzheimer's Disease, outside the submitted work. B. V. is the Founding President of IHU HealthAge (ANR-23-IAHU-0011), affiliated with Toulouse University Hospital and Inserm Cerpop. He is also an investigator in clinical trials sponsored by several industry partners. In the past three years, he has served as a Scientific Advisory Board (SAB) member for Biogen, Alzheon, Novo Nordisk, Lilly, Eisai, and Roche, without any personal compensation. J.C. has provided consultation to Acadia, Acumen, ALZpath, Annovis, Aprinoia, Artery, Axsome, Biogen, Biohaven, BioXcel, Bristol-Myers Squib, Cervomed, Eisai, Fosun, GAP Foundation, Green Valley, IGC, Janssen, Kinoxis, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, NSC Therapeutics, Optoceutics, Otsuka, Oxford Brain Diagnostics, Praxis, Prothena, ReMYND, Roche, Scottish Brain Sciences, Signant Health, Simcere, Sinaptica, T-Neuro, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. He has stocks/options in Artery, Vaxxinity, Behrens, Alzheon, MedAvante-Prophase, Acumen. He is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P30AG072959; NIA grant R35AG71476; NIA R25 AG083721–01; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers-Grundy Endowment. J.C. owns the copyright to the Neuropsychiatric Inventory (NPI).

Figures

Fig 1
Fig. 1
Key points addressed by the EU/US CTAD task force.
Fig 2
Fig. 2
Combination therapy clinical trials designs. Adapted from R. Raman presentation « Statistical Issues in combination drug trials » CTAD Task Force 2024.
See this image and copyright information in PMC

References

    1. Hampel H., Hu Y., Hardy J., et al. The amyloid-β pathway in Alzheimer's disease: a plain language summary. Neurodegener Dis Manag. 2023;13(3):141–149. doi: 10.2217/nmt-2022-0037. - DOI - PMC - PubMed
    1. van Dyck C.H., Swanson C.J., Aisen P., et al. Lecanemab in early Alzheimer's Disease. N Engl J Med. 2023;388(1):9–21. doi: 10.1056/NEJMoa2212948. - DOI - PubMed
    1. Sims J.R., Zimmer J.A., Evans C.D., et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–527. doi: 10.1001/jama.2023.13239. - DOI - PMC - PubMed
    1. Angioni D., Cummings J., Lansdall C.J., et al. Clinical meaningfulness in Alzheimer's Disease Clinical trials. A report from the EU-US CTAD Task Force. J Prev Alzheimers Dis. 2024;11(5):1219–1227. doi: 10.14283/jpad.2024.112. - DOI - PMC - PubMed
    1. Zhang J., Zhang Y., Wang J., et al. Recent advances in Alzheimer's disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther. 2024;9(1):211. doi: 10.1038/s41392-024-01911-3. Published 2024 Aug 23. - DOI - PMC - PubMed