APP and Alzheimer disease: To summarize, we list the current outstanding problems of Aβ oligomers toxicity as follow: (1) deciphering the unknown transmembrane structure of APP; (2) uncovering the configurational and structural diversity of Aβ oligomers; (3) elucidating the pathogenesis of intraneuronal Aβ accumulation; and (4) curing Alzheimer’s disease by directing the best antibodies at Aβ peptides.