APP and early-onset autosomal dominant Alzheimer disease: The amyloid hypothesis for Alzheimer’s disease (AD) posits a neuron-centric, linear cascade initiated by the abnormal production of longer amyloid β peptide (Aβ) forms, especially Aβ1-42, from amyloid precursor protein (APP); this leads progressively to tau pathology, synaptic dysfunction, inflammation, neuronal loss, and ultimately dementia1.