The amyloid cascade hypothesis: an updated critical review

Abstract

Results from recent clinical trials of antibodies that target amyloid-β (Aβ) for Alzheimer's disease have created excitement and have been heralded as corroboration of the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging and biochemical data suggest a more complex aetiology. Here we review the history and weaknesses of the amyloid cascade hypothesis in view of the new evidence obtained from clinical trials of anti-amyloid antibodies. These trials indicate that the treatments have either no or uncertain clinical effect on cognition. Despite the importance of amyloid in the definition of Alzheimer's disease, we argue that the data point to Aβ playing a minor aetiological role. We also discuss data suggesting that the concerted activity of many pathogenic factors contribute to Alzheimer's disease and propose that evolving multi-factor disease models will better underpin the search for more effective strategies to treat the disease.

Keywords: Alzheimer’s disease; aducanumab; amyloid cascade hypothesis; lecanemab; β-amyloid.