[Comment] From patients to disease: the difficult case of Alzheimer's

The accumulation of fibrillar amyloid ? in the cortex, followed by the deposition of fibrillar hyper-phosphorylated tau, neurodegenerative changes, and cognitive impairment have been identified as biological drivers of Alzheimer's disease. This mechanistic sequence of events, known as the amyloid cascade hypothesis, has been largely informed by observations in very rare autosomal dominant cases, in which all mutations are in genes (ie, PSEN1, PSEN2, and APP) that have protein products involved in the metabolism of amyloid ?.