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Editorials

Solanezumab and the amyloid hypothesis for Alzheimer’s disease

BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i6771 (Published 29 December 2016) Cite this as: BMJ 2016;355:i6771
  1. David G Le Couteur, professor of geriatric medicine1,
  2. Sally Hunter, research associate2,
  3. Carol Brayne, professor of public health2
  1. 1Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Sydney, Australia
  2. 2Cambridge Institute of Public Health, Cambridge, UK
  1. Correspondence to: D G Le Couteur david.lecouteur{at}sydney.edu.au

Solanezumab’s failure is a wake-up call to look elsewhere for an answer to dementia

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 …

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