The present study suggests approaches to construct adequate transgenic animal models of AD, advocates for the advantages of human neuronal cells-based AD models, makes verifiable predictions, indicates that the production of BACE1 and BACE2, and even of γ-secretase, can also be suppressed in the AD-affected neurons, proposes that the disease may be driven by C99 generated independently of AβPP, and discusses the potential therapeutic implication of its conclusions. Here, APP is linked to Alzheimer disease.