β-amyloid: The known unknowns.

Alzheimer's disease (AD) stands out as a major disease without any form of preventative or disease modifying therapy. This is not for lack of trying. 33 phase 3 clinical trials of drugs targeting amyloid beta (Aβ) have failed to slow cognitive decline in AD. The field is at a cross-roads about whether to continue anti-Aβ therapy or more actively pursue alternative targets. With the burden of this disease to patients, families, and healthcare budgets growing yearly, the need for disease modifying AD therapies has become one of the highest priorities in all of medicine. While pathology, genetic and biochemical data offer a popular narrative for the causative role of Aβ, there are alternative explanations, and dissenting findings that, now more than ever, warrant thorough reanalysis. This review questions the major assumptions about Aβ on which therapies for AD were premised, and invites renewed interrogation into AD pathogenesis.