Solanezumab and the amyloid hypothesis for Alzheimer’s disease

Is the amyloid cascade hypothesis of Alzheimer’s disease too big to fail?1 It proposes that brain deposition of β amyloid protein is the critical early event in the pathogenesis of Alzheimer’s disease and has been the centrepiece of dementia research for decades.2 The hypothesis suggests that removing β amyloid will reverse or prevent the clinical expression of dementia. However, in all phase III clinical trials to date, treatments targeting β amyloid have failed to improve cognitive outcomes despite reducing brain β amyloid.3

It is widely argued that these negative trials do not disprove the hypothesis but that treatments should be given decades earlier before β amyloid has “caused” neuronal loss, or that the trials had included people without amyloid deposits.2 The results of a third trial investigating solanezumab (EXPEDITION3), a monoclonal antibody targeting amyloid plaques, were therefore eagerly awaited after the first two trials had negative results but with post hoc indications of potential effects on …