Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of Aβ at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease Aβ in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.