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  • Perspective
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The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

Nature Reviews Neurology volume 17, pages 703–714 (2021)Cite this article

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Abstract

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform ‘go–no-go’ decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.

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Fig. 1: Stopping amyloid accumulation: slow and steady.

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Acknowledgements

The authors thank the many thousands of participants and study partners worldwide who have participated in β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) inhibitor clinical trials. Without their altruism and bravery, the understanding of BACE inhibition as a therapeutic strategy for Alzheimer disease would not have progressed nearly so rapidly.

Author information

Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    Eric McDade & Randall J. Bateman

  2. Department of Neurosciences, KU Leuven, Leuven, Belgium

    Iryna Voytyuk & Bart De Strooper

  3. Centre for Brain and Disease Research, VIB (Flanders Institute for Biotechnology), Leuven, Belgium

    Iryna Voytyuk & Bart De Strooper

  4. ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK

    Iryna Voytyuk

  5. Alzheimer’s Therapeutic Research Institute, University of Southern California, Los Angeles, CA, USA

    Paul Aisen

  6. Alzheimer’s Association, Chicago, IL, USA

    Maria C. Carrillo

  7. Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, UK

    Bart De Strooper

  8. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Christian Haass & Stefan F. Lichtenthaler

  9. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Christian Haass & Stefan F. Lichtenthaler

  10. Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

    Christian Haass

  11. Banner Alzheimer’s Institute, Phoenix, AZ, USA

    Eric M. Reiman & Pierre N. Tariot

  12. Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Reisa Sperling

  13. Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA

    Riqiang Yan

  14. The Florey Institute, The University of Melbourne, Parkville, VIC, Australia

    Colin L. Masters

  15. Davee Department of Neurology, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Robert Vassar

  16. Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

    Stefan F. Lichtenthaler

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Contributions

E.M., R.V. and S.F.L. researched data for the article, contributed substantially to the discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. I.V. and R.Y. contributed substantially to the discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. E.M.R., R.J.B., B.D.S., C.H., R.S., P.N.T. and C.L.M. contributed substantially to the discussion of the content and reviewed and/or edited the manuscript before submission. M.C.C. and P.A. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Eric McDade, Robert Vassar or Stefan F. Lichtenthaler.

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Competing interests

There were no sources of funding that directly supported this work. E.M. reports serving on a data safety committee for Eli Lilly and Company, personal honoraria for continuing medical education activities for Eisai and Eli Lilly and Company and UpToDate, and institutional grant support from Eli Lilly and Company, Hoffman-La Roche and Janssen. P.A. has research grants from Eisai, Eli Lilly and Company and Janssen pharmaceuticals, and has received consulting fees from Biogen, Hoffman-La Roche, ImmunoBrain Checkpoint, Merck & Co. and Samus. R.J.B. serves as the principal investigator of the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU), which is supported by the Alzheimer’s Association, the GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (active: Biogen, Eisai, Eli Lilly and Company/Avid Radiopharmaceuticals, Hoffman-La Roche/Genentech, Janssen and United Neuroscience; previously: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer and Sanofi). The DIAN-TU-001 clinical trial is supported by pharmaceutical partners Eli Lilly and Company, Hoffman-La Roche and Janssen, the Alzheimer’s Association, Avid Radiopharmaceuticals, the GHR Foundation, US National Institutes of Health (NIH) project U01AG042791, NIH project U01AG42791-S1 (Foundation for the National Institutes of Health Accelerating Medicines Partnership), NIH project R01AG046179, NIH project R56AG053267, NIH project R01AG053267, NIH project R01AG053267-S1, NIH project R01AG053267-S2, NIH project U01AG059798 and an anonymous organization. In-kind support has been received from Bracket and CogState for DIAN-TU-001. R.J.B. has received honoraria as a speaker and/or consultant and/or advisory board member from Amgen, AC Immune, Eisai, Hoffman-LaRoche, Janssen and Pfizer and reimbursement of travel expenses from AC Immune, Hoffman-La Roche and Janssen. R.J.B. receives laboratory research funding from the Alzheimer’s Association, the Association for Frontotemporal Degeneration, the BrightFocus Foundation, the Cure Alzheimer’s Fund, Centene Corporation, the NIH, the Rainwater Foundation Tau Consortium, the Tau SILK Consortium (AbbVie, Biogen and Eli Lilly and Company) and an anonymous foundation. R.J.B. is a cofounder of and serves on the scientific advisory board for C2N Diagnostics LLC. Washington University also holds equity in C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. Washington University, R.J.B. and D. Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labelling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with R.J.B. as a co-inventor, has submitted the US non-provisional patent application “Methods for measuring the metabolism of CNS derived biomolecules in vivo” and the provisional patent application “Plasma based methods for detecting CNS amyloid deposition”. B.D.S. has received research support from Esai and Janssen pharmaceuticals. C.H. reports collaborations with Denali Therapeutics Inc., has participated in one advisory board meeting of Biogen and has received a speaker honorarium from Novartis and Roche. C.H. is the chief adviser to ISAR Bioscience. E.M.R. is one of the leaders of the Alzheimer’s Prevention Initiative, which worked closely with Amgen and Novartis in Alzheimer’s Prevention Initiative Generation Study 1 and Generation Study 2. These trials were funded by Amgen, the US National Institute on Aging, Novartis and philanthropy. E.M.R. is an unpaid scientific adviser to Avid Radiopharmaceuticals, a subsidiary of Eli Lilly and Company. R.S. has research grants from Eli Lilly and Company, Eisai and Janssen pharmaceuticals. P.N.T. has received consulting fees from Acadia, AC Immune, Axsome, BioXcel, Boehringer-Ingelheim, Brain Test Inc., Eisai, eNOVA, the Gerontological Society of America, Otuska & Astex and Syneos, consulting fees and research support from Abbvie, Avanir, Biogen, Cortexyme, Genentech, Eli Lilly and Company, Merck & Co. and Roche and research support from Novartis and has stock ownership in Adamas Pharmaceuticals, which has no past, current or known future involvement in any β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) inhibitor-related therapies or clinical trials. R.V. has stock options in Alector given for his service on the scientific advisory board. R.V.’s advisory relationship with Alector does not involve BACE1 inhibition as a therapeutic strategy. R.V. has consulted for Eisai and Novartis in the past, but is not doing so currently. S.F.L. reports research funding from Novartis and Shionogi. The other authors report no relevant disclosures.

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Nature Reviews Neurology thanks M. Boada, T. Golde, C. Ritchie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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McDade, E., Voytyuk, I., Aisen, P. et al. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol 17, 703–714 (2021). https://doi.org/10.1038/s41582-021-00545-1

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