Notable failures of amyloid-β-targeted therapies in late-stage clinical trials for Alzheimer disease (AD) suggest the need for a reassessment of the amyloid cascade hypothesis of AD pathology. Here, Giacobini and Gold discuss the limitations of focusing on amyloid-β, and suggest a shift towards tau-directed therapy. They outline the rationale for such an approach and summarize results in animal models that show promise for translation to the clinic.