The amyloid cascade hypothesis—in which the age‐dependent accumulation of the amyloid β‐peptide (Aβ) is proposed to be the trigger for Alzheimer disease—has provided a huge impetus for research into disease mechanisms and contributed to the focusing of research on to Alzheimer disease therapeutics. Aβ itself is derived from the transmembrane amyloid precursor protein (APP), the gene for which was the first to be linked with early onset Alzheimer disease exactly 20 years ago (Goate et al , 1991). Most subsequent therapeutic strategies have focused on modifying the formation, aggregation or removal of Aβ. Yet, two decades on, treatments remain limited and they are palliative, rather than curative for the disease. This suggests a missing link in the chain from disease initiation to cognitive decline and death. The focus on amyloid accumulation has therefore detracted from attempts to understand the normal functions of APP. It might be that a loss of normal APP metabolism and physiology, as much as a gain in Aβ toxicity, could contribute to the development …