Equally important, while the toxicity of Aβ is undeniable, we suggest a role for elevated C99 (Rockenstein et al, 2005) and MAM deregulation (Schon & Area‐Gomez, 2010, 2013) in the pathogenesis of the disease, thus providing a new framework for understanding the link between alterations in APP processing and lipid homeostasis as seminal effectors of AD pathogenesis. Here, APP is linked to Alzheimer disease.