The amyloid cascade hypothesis posits that the deposition of the amyloid-β peptide in the brain parenchyma is a crucial step in Alzheimer's disease (AD). This concept has influenced and guided much of the academic and pharmaceutical research carried out during the past twenty years.
However, several therapeutic agents that purport to reduce the production or aggregation of the amyloid-β peptide have failed in Phase III clinical trials and this has brought an increased focus to this area of research.
Two crucial questions must therefore be considered: by how much should a therapeutic agent inhibit amyloid-β production, or facilitate amyloid-β clearance; and at what stage in the disease process should such a therapeutic agent be administered, to produce a disease-modifying effect in AD?
This article re-evaluates the amyloid cascade hypothesis and reviews relevant preclinical, clinical and genetic data. In particular, autosomal dominant familial AD is used to distinguish between the effects of amyloid-β deposition on the age of disease onset and the duration of the disease.
A strong case can be made that the deposition of amyloid-β in the brain parenchyma is crucial for initiating the disease process, but there are no compelling data to support the view that, once initiated, the disease process is continuously driven by or requires amyloid-β deposition.
Four scenarios that describe the potential role of amyloid-β in AD are described: amyloid-β trigger; amyloid-β threshold; amyloid-β driver; and amyloid-β irrelevant. Whether current and future amyloid-β-centric therapeutics will show clinical efficacy will crucially depend on which of these scenarios most accurately reflects the AD process
The amyloid cascade hypothesis, which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-β production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.
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B.D.S. is the Bax-Vanluffelen Chair for Alzheimer's Disease and is supported by a Methusalem grant (FWO-Flanders). The authors would like to thank S. M. Paul and J. Hardy for their careful reading of the manuscript.
Bart De Strooper is a consultant for Janssen Pharmaceutica in Beerse, Belgium; Envivo Pharmaceuticals in Boston, Massachusetts, USA; and Remynd NV in Leuven, Belgium. He also receives research funding from Janssen Pharmaceutica, Beerse.
Mark Mercken is currently employed by Janssen Pharmaceutica, and holds stock in Johnson and Johnson.
Eric Karran is currently employed by Janssen Pharmaceutica, and holds stock in Johnson and Johnson.
Amyloid-β peptides result from sequential cleavage of the amyloid precursor protein by β-cleaving amyloid precursor protein enzyme (BACE) and γ-secretase. These peptides vary in length, with Aβ40 (the 40-amino acid form of the peptide) being predominant.
- Amyloid plaques
Amyloid plaques are deposits of insoluble amyloid-β in the parenchyma of the brain that can be diffuse or compact. If they are associated with dystrophic and degenerating neurons, they are often termed 'neuritic plaques'.
- Neurofibrillary tangles
Large deposits of hyperphosphorylated tau (5–9 moles of phosphate per mole of tau) that fill the cell body of the neuron and take its shape. They are composed of both paired helical and straight filaments of hyperphosphorylated tau.
A protein that binds to and stabilizes microtubules within cells and is abundant in neurons. Humans express six isoforms of tau that result from alternative splicing of exons 2, 3 and 10 of the tau gene. Tau can be multiphosphorylated and this regulates its microtubule-binding properties.
- Apolipoprotein E
(APOE). A 34-kDa secreted protein that is synthesized predominantly in the liver but is also produced by glial cells in the brain. It acts as a lipoprotein-binding protein and mediates lipid metabolism by binding to the low-density lipoprotein superfamily of receptors.
- Genome-wide association (GWA) studies
This technique enables common, single-nucleotide polymorphic genetic variations to be compared in patients and in controls, to discover whether there is evidence for a genetic predisposition to the disease.
- Familial Alzheimer's disease
(FAD). A form of Alzheimer's disease (AD) caused by rare, autosomal dominant mutations that are inherited in a Mendelian fashion within families. Currently identified FAD mutations result in early-onset AD.
- Paired helical filaments
Hyperphosphorylated tau filaments that can be visualized in neurons using electron microscopy.
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Karran, E., Mercken, M. & Strooper, B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10, 698–712 (2011). https://doi.org/10.1038/nrd3505
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