Publications

Abstract

The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. Here we review why accumulation of amyloid-beta (AB) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We then elaborate on and update arguments for and against the amyloid cascade hypothesis with new data and interpretations, and consider why the amyloid hypothesis is failing therapeutically. We note several unresolved issues in the field including the presence of AB deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, the unclear biochemical nature and presence of AB oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the failure of the amyloid cascade hypothesis to explain pathological heterogeneity and comorbidities. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease and amyloid precursor protein (APP) processing, can be interpreted independently of a role for AB in AD. Furthermore, we review emerging evidence that AB has an essential physiological nontoxic role in the brain, for example, in memory formation. We conclude it is essential to expand our view of pathogenesis beyond AB, and also tau pathology, and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.