Volume 18, Issue 12 p. 2687-2698
THEORETICAL ARTICLE

Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease

Johannes Levin

Johannes Levin

Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany

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

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

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Jonathan Vöglein

Jonathan Vöglein

Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany

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

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Yakeel T. Quiroz

Yakeel T. Quiroz

Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA

Grupo de Neurociencias, Universidad de Antioquia, Antioquia, Colombia

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Randall J. Bateman

Randall J. Bateman

Washington University School of Medicine, Saint Louis, Missouri, USA

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Valentina Ghisays

Valentina Ghisays

Banner Alzheimer's Institute, Phoenix, Arizona, USA

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Francisco Lopera

Francisco Lopera

Grupo de Neurociencias, Universidad de Antioquia, Antioquia, Colombia

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Eric McDade

Eric McDade

Washington University School of Medicine, Saint Louis, Missouri, USA

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Eric Reiman

Eric Reiman

Banner Alzheimer's Institute, Phoenix, Arizona, USA

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Pierre N. Tariot

Pierre N. Tariot

Banner Alzheimer's Institute, Phoenix, Arizona, USA

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John C. Morris

Corresponding Author

John C. Morris

Washington University School of Medicine, Saint Louis, Missouri, USA

Correspondence

John C. Morris, Washington University School of Medicine, 4488 Forest Park Ave, Suite 200, St. Louis, MO 63108, USA.

E-mail: [email protected]

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First published: 24 February 2022
Citations: 8

Johannes Levin, Jonathan Vöglein, and Yakeel T. Quiroz are co-first authors.

Abstract

Objective

The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia.

Background

An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits.

Updated Hypothesis

It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies.

Major Challenges for the Hypothesis

Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late-onset AD.

Linkage to Other Major Theories

The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.

CONFLICTS OF INTEREST

Johannes Levin reports speaker fees from Bayer Vital, Biogen, and Roche; consulting fees from Axon Neuroscience and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; non-financial support from Abbvie; and compensation for duty as part-time CMO from MODAG, outside the submitted work. Jonathan Vöglein reports consulting fees from Eisai, outside the submitted work. Yakeel T. Quiroz reports receiving consulting fees from Biogen, outside the submitted work, and reports receiving funds by grants from the NIH Office of the Director (DP5OD019833), NIH NIA (R01AG054671), the Alzheimer's Association, and Massachusetts General Hospital ECOR (1200-228010 and 1200-228767). Randall J. Bateman reports the following: sources of research support: NIH R01NS065667, NIH UF1AG032438 (DIAN), NIH U01AG042791 (DIAN-TU), NIH U01AG042791-S1 (DIAN-TU), NIH R1AG046179 (DIAN-TU-APT), Alzheimer's Association, BrightFocus Foundation, GHR Foundation, Anonymous Foundation, DIAN-TU Pharma Consortium, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly, Forum, Janssen AIP, Pfizer, Roche, and Sanofi-Aventis; companies: cofounder C2N Diagnostics; invited speaker: Biogen and EMA; editorial board: Alzheimer's Research and Therapy and The Journal of Prevention of Alzheimer's Disease; consulting relationships: Abbvie, Boehringer-Ingelheim, Forum (En Vivo) Scientific Advisory Board, and Global Alzheimer's Platform. Valentina Ghisays reports no conflicts of interest. Francisco Lopera reports no conflicts of interest and reported receiving funds by grants from the NIH, Genentech/Roche for API Colombia, COLCIENCIAS and Massachusetts General Hospital. Eric McDade reports grants from NIA, non-financial support from Elli Lilly, non-financial support from Roche, personal fees from Elli Lilly, outside the submitted work. Eric Reiman reports grants from The National Institute on Aging, Novartis/Amgen, Banner Alzheimer's Foundation, Alzheimer's Association, GHR Foundation, F-Prime Biosciences Research Initiative, and NOMIS Foundation. He also reports that he is a compensated scientific advisor with: Alkahest, Alzheon, Axovant, Denali, Green Valley, United Neuroscience and Zinfandel Pharma. Banner Alzheimer's Institute has contracts with Genentech/Roche, Novartis/Amgen, and Avid/Lilly. Pierre Tariot reports receiving consulting fees from Abbott Laboratories, AbbVie, AC Immune, Acadia, Auspex, Boehringer Ingelheim, Chase Pharmaceuticals, Corium, Eisai, GliaCure, INSYS Therapeutics, Pfizer, and T3D; receiving consulting fees and research support from AstraZeneca, Avanir, Biogen, Cognoptix, Eli Lilly, H. Lundbeck A/S, Merck and Company, Roche, and Takeda; receiving research support only from Amgen, Avid, Functional Neuromodulation, GE Healthcare, Genentech, Novartis, Roche, Targacept, the National Institute on Aging, and the Arizona Department of Health Services; owning stock options in Adamas; and being listed as a contributor to a patent owned by the University of Rochester. J. C. Morris is funded by NIH grants # P50AG005681, P01AG003991, P01AG026276, and UF1AG032438. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company.