APP and Alzheimer disease: Given the many inputs to the APP signaling balance in humans (e.g., estrogen, netrin-1, Aβ, etc.), and the minimal success with each of many potentially therapeutic agents (e.g., estrogen, melatonin, exercise, vitamin D, curcumin, Ashwagandha, etc.), the pathobiology of AD dictates a system or program rather than a single targeted agent.