John Hardy suggested the build-up of amyloid as a cause of Alzheimer's disease more than 25 years ago. In brains with Alzheimer's disease, abnormal amounts of the naturally occurring amyloid protein clump together to form plaques that collect between neurons and disrupt cell function. The role of amyloid is clear. But therapeutic investigations were disappointing. John Hardy discusses the state of Alzheimer's research today, and new approaches are being considered with amyloid and other mechanisms that may play a role in Alzheimer's disease.