Amyloid β-protein and beyond: the path forward in Alzheimer’s disease

•Lack of success of most anti-amyloid trials in symptomatic AD is attributable in part to the pathology being too advanced.•Progress in quantifying tau and Aβ in plasma suggests that changes in these analytes may even predict AD presymptomatically.•Anti-Aβ immunotherapy should include secondary prevention trials as well as anti-tau and genetic downregulation of APP or tau.•Proving tau pathogenic spread requires elucidating release, uptake & cytosol entry and also assessing diffusible metabolites. Basic research on the biological mechanism of Alzheimer’s disease has focused for decades on the age-related aggregation of the amyloid β-protein and its apparent downstream effects on microglia, astrocytes and neurons, including the posttranslational modification of the tau protein that seems necessary for symptom expression. Here, we discuss the highly challenging process of developing disease-modifying therapies and highlight several key areas of current research that are progressing in exciting directions. We conclude that further deep molecular analyses of the disease, including the mechanisms of β-amyloidosis, will enable more effective clinical trials and ultimately achieve the progress that our patients so deserve.