Combination Therapy for Alzheimer’s Disease: Perspectives of the EU/US CTAD Task Force

  • Serge GauthierEmail author
  • J. Alam
  • H. Fillit
  • T. Iwatsubo
  • H. Liu-Seifert
  • M. Sabbagh
  • S. Salloway
  • C. Sampaio
  • J. R. Sims
  • B. Sperling
  • R. Sperling
  • K. A. Welsh-Bohmer
  • J. Touchon
  • B. Vellas
  • P. Aisen
  • EU/US/CTAD Task Force
CTAD Task Force Paper


Combination therapy is expected to play an important role for the treatment of Alzheimer’s disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches.

Key words

Alzheimer’s disease amyloid tau therapeutics trial design 


  1. 1.
    Hendrix JA, Bateman RJ, Brashear HR, et al. Challenges, solutions, and recommendations for Alzheimer’s disease combination therapy. Alzheimers Dement 2016;12:623–630.CrossRefGoogle Scholar
  2. 2.
    Perry D, Sperling R, Katz R, et al. Building a roadmap for developing combination therapies for Alzheimer’s disease. Expert Rev Neurother 2015;15:327–333.CrossRefGoogle Scholar
  3. 3.
    Stephenson D, Perry D, Bens C, et al. Charting a path toward combination therapy for Alzheimer’s disease. Expert Rev Neurother 2015;15:107–113.CrossRefGoogle Scholar
  4. 4.
    Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 2018;14:367–429.CrossRefGoogle Scholar
  5. 5.
    Alzheimer’s Disease International. World Alzheimer’s Report 2018. The state of the art of dementia research: New frontiers. London 2018.Google Scholar
  6. 6.
    Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (N Y) 2017;3:367–384.Google Scholar
  7. 7.
    Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical, cognitive, and biomarker changes in the Dominantly Inherited Alzheimer Network. The New England journal of medicine 2012;367:795–804.CrossRefGoogle Scholar
  8. 8.
    Schindler RJ. Study design considerations: conducting global clinical trials in early Alzheimer’s disease. J Nutr Health Aging 2010;14:312–314.CrossRefGoogle Scholar
  9. 9.
    Sperling R, Cummings J, Donohue M, Aisen P. Global Alzheimer’s Platform Trial Ready Cohorts for the Prevention of Alzheimer’s Dementia. J Prev Alzheimers Dis 2016;3:185–187.Google Scholar
  10. 10.
    Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016;8:595–608.CrossRefGoogle Scholar
  11. 11.
    Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 2012;488:96–99.CrossRefGoogle Scholar
  12. 12.
    Serrano-Pozo A, Betensky RA, Frosch MP, Hyman BT. Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. Am J Pathol 2016;186:375–384.CrossRefGoogle Scholar
  13. 13.
    Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 2012;15:349–357.CrossRefGoogle Scholar
  14. 14.
    O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011;34:185–204.CrossRefGoogle Scholar
  15. 15.
    Sims JR, Selzler KJ, Downing AM, et al. Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). J Prev Alzheimers Dis 2017;4:247–254.Google Scholar
  16. 16.
    Budd Haeberlein S, O’Gorman J, Chiao P, et al. Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer’s Disease. J Prev Alzheimers Dis 2017;4:255–263.Google Scholar
  17. 17.
    Jack CR, Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14:535–562.CrossRefGoogle Scholar
  18. 18.
    Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018;4:195–214.Google Scholar
  19. 19.
    Hara Y, McKeehan N, Fillit HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology 2019;92:84–93.CrossRefGoogle Scholar
  20. 20.
    Jack CR, Jr., Knopman DS, Weigand SD, et al. An operational approach to National Institute on Aging-Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann Neurol 2012;71:765–775.CrossRefGoogle Scholar
  21. 21.
    Tomaszewski S, Gauthier S, Wimo A, Rosa-Neto P. Combination Therapy of Anti-Tau and Anti-Amyloid Drugs for Disease Modification in Early-stage Alzheimer’s Disease: Socio-economic Considerations Modeled on Treatments for Tuberculosis, HIV/AIDS and Breast Cancer. J Prev Alzheimers Dis 2016;3:164–172.Google Scholar
  22. 22.
    Hendrix S, Ellison N, Stanworth S, Otcheretko V, Tariot PN. Post Hoc Evidence for an Additive Effect of Memantine and Donepezil: Consistent Findings from DOMINO-AD Study and Memantine Clinical Trial Program. J Prev Alzheimers Dis 2015;2:165–171.Google Scholar
  23. 23.
    Bateman RJ, Benzinger TL, Berry S, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimers Dement 2017;13:8–19.CrossRefGoogle Scholar
  24. 24.
    Saville BR, Berry SM. Efficiencies of platform clinical trials: A vision of the future. Clin Trials 2016;13:358–366.CrossRefGoogle Scholar
  25. 25.
    Food and Drug Administration. Guidance for industry: Codevelopment of two or more unmarketed investigational drugs for use in combination.. Accessed online 4/13/14 at, 2013.Google Scholar
  26. 26.
    Irizarry MC, Fleisher AS, Hake AM, et al. TRAILBLAZER-ALZ (NCT03367403): A Phase 2 disease-modification combination therapy trial targeting multiple mechanisms of action along the amyloid pathway. Alzheimer Dement 2018;14:P1622–P1623.CrossRefGoogle Scholar
  27. 27.
    DeMattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron 2012;76:908–920.CrossRefGoogle Scholar
  28. 28.
    DeMattos R, May P, Racke M, et al. Combination therapy with a plaque-specific Abeta antibody and BACE inhibitor results in dramatic plaque lowering in aged PDAPP transgenic mice. Alzheimer Dement 2014;10:P149.CrossRefGoogle Scholar
  29. 29.
    Wessels AM, Siemers ER, Yu P, et al. A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer’s Disease Rating Scale (iADRS). J Prev Alzheimers Dis 2015;2:227–241.Google Scholar
  30. 30.
    Panza F, Lozupone M, Solfrizzi V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev Neurother 2018;18:847–857.CrossRefGoogle Scholar
  31. 31.
    Vellas B, Bain LJ, Touchon J, et al. Advancing Alzheimer’s Disease Treatment: Lessons from CTAD 2018. J Prev Alzheimers Dis. 2019; in pressGoogle Scholar

Copyright information

© Serdi and Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Serge Gauthier
    • 1
    Email author
  • J. Alam
    • 2
  • H. Fillit
    • 3
  • T. Iwatsubo
    • 4
  • H. Liu-Seifert
    • 5
  • M. Sabbagh
    • 6
  • S. Salloway
    • 7
  • C. Sampaio
    • 8
  • J. R. Sims
    • 5
  • B. Sperling
    • 9
  • R. Sperling
    • 10
  • K. A. Welsh-Bohmer
    • 11
  • J. Touchon
    • 12
    • 13
  • B. Vellas
    • 14
  • P. Aisen
    • 15
  • EU/US/CTAD Task Force
  1. 1.McGill Center for Studies in AgingVerdunCanada
  2. 2.EIP Pharma Inc.CambridgeUSA
  3. 3.The Alzheimer’s Drug Discovery FoundationNew YorkUSA
  4. 4.University of TokyoTokyoJapan
  5. 5.Eli Lilly and CompanyIndianapolisUSA
  6. 6.L Cleveland Clinic Lou Ruvo Center for Brain HealthLas VegasUSA
  7. 7.The Warren Alpert Medical School of Brown UniversityProvidenceUSA
  8. 8.CHDI FoundationPrincetonUSA
  9. 9.LundbeckCopenhagenDenmark
  10. 10.Brigham and Women’s HospitalBostonUSA
  11. 11.Duke UniversityDurhamUSA
  12. 12.University Hospital of MontpellierMontpellier Cedex 5France
  13. 13.INSERM 1061MontpellierFrance
  14. 14.Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical CenterToulouse University HospitalToulouseFrance
  15. 15.Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of MedicineUniversity of Southern CaliforniaSan DiegoUSA

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