The Amyloid Cascade Hypothesis for Alzheimer'S Disease: an Appraisal for the Development of Therapeutics

Key Points 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