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. The gene discussed is BACE2; the disease is Alzheimer disease.