APP and Alzheimer disease: Although the initiating event with respect to amyloid deposition in AD is the excess production of Aβ peptides, multiple pharmacological inhibitors of BACE1 and γ-secretase—the enzymes that sequentially cleave these peptides from APP—have failed as AD therapies, often because of adverse off-target effects (Coric et al., 2015; Das and Yan, 2019).