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A new roadmap for drug development for Alzheimer's disease

Nature Reviews Drug Discovery volume 13, page 156 (2014)Cite this article

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An article in Nature Reviews Drug Discovery (Nature Rev. Drug Discov. 11, 657–660; 2012)1 reported that three prevention trials (known as API, DIAN and A4) in patients with asymptomatic Alzheimer's disease (AD) hope, with biomarker and cognitive changes, to validate the amyloid hypothesis and set the stage for AD drug approvals. A response (Nature Rev. Drug Discov. 12, 324; 2013)2 endorsed the plans in this earlier report.

Here, we question the wisdom of this step for these trials and another proposed study (known as DSBI) (Table 1). As currently designed, we consider that AD drug development trials have four important deficiencies. First, without the addition of aims to test specific mechanistic hypotheses that are able to explain the conditions necessary to modify the course of AD, these clinical trials will not advance our knowledge of AD neuropathologies and their roles in progression to symptomatic AD. Second, knowledge of how the timing of neuropathologies may affect the successful use of agents that target the 42-amino-acid form of the amyloid-β peptide (Aβ42) or other AD drugs will not advance. Third, a potentially useful drug may be abandoned owing to lack of clinical efficacy. Fourth, drug effects on symptoms may be misinterpreted as evidence for disease modification.

Table 1 Selected trials of amyloid-β (Aβ)-targeted interventions for Alzheimer's disease (AD)*
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Authors and Affiliations

  1. Robert E. Becker, M.D., C.M., is the President of Aristea Translational Medicine, 5011 Mountain View Road #63, Carrabassett Valley, Maine O4947, USA, and a Clinical Consultant in the Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.,

    Robert E. Becker

  2. Nigel H. Greig, Ph.D., is a Senior Investigator in the Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore Maryland 21224, USA.,

    Nigel H. Greig

  3. is a professor in the Department of Internal Medicine, Ezio Giacobini, M.D., Ph.D., Rehabilitation, and Geriatrics, University of Geneva, Medical School, University Hospitals of Geneva, Thonex-Geneva, Switzerland.,

    Ezio Giacobini

  4. is a professor in the Departments of Psychiatry, Lon S. Schneider, M.D.,M.S., Neurology, and Gerontology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.,

    Lon S. Schneider

  5. Luigi Ferrucci, M.D., Ph.D., is the Scientific Director of the Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.,

    Luigi Ferrucci

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  1. Robert E. Becker
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  2. Nigel H. Greig
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Corresponding author

Correspondence to Robert E. Becker.

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Competing interests

R.E.B. received no funding to support this manuscript. R.E.B. is the President of Aristea Translational Medicine, a company that has developed Preemptive Error Management guides to avoid error intrusions able to undermine the validity of drug developments and proposes to carry out clinical trials to test AR-YU-69 for efficacy in Alzheimer's disease (AD).

N.H.G. and L.F. are employees of the National Institute of Aging but received no other funding.

N.H.G. was an inventor on a number patents for experimental drugs for use in AD that all are assigned to the United States Public Health Service.

L.S.S. is supported in part by NIH grants R01AG037561, R01AG033288 and P50 AG05142, and State of California 09–11413 and received no other funding to support this manuscript. L.S.S. reports being an editor on the Cochrane Collaboration Dementia and Cognitive Improvement Group, which oversees systematic reviews of drugs for cognitive impairment and dementia; receiving a grant from the Alzheimer's Association for a registry for dementia and cognitive impairment trials; receiving grant or research support from Baxter, Eli Lilly, Genentech, Novartis, Pfizer, and Tau Rx; and having served as a consultant for or receiving consulting fees from AC Immune, Allon, AstraZeneca, Baxter, BiogenIdec, Chiesi, Elan, Eli Lilly, GlaxoSmithKline, Ispen, Johnson & Johnson, Lundbeck, Merck, Pfizer, Roche, Takeda, Toyama, and Zinfandel.

L.F. reports no financial conflicts of interest.

E.G. received no funding to support this manuscript. E.G. reports no conflicts of interest.

Each author contributed equally to the conceptualization and preparation of this manuscript.

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Becker, R., Greig, N., Giacobini, E. et al. A new roadmap for drug development for Alzheimer's disease. Nat Rev Drug Discov 13, 156 (2014). https://doi.org/10.1038/nrd3842-c2

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