APP and Alzheimer disease: In this study, we developed the hPSC-derived BOs and demonstrated the BOs with HSCR-associated BACE2 loss-of-function mutation exhibited AD-like phenotypes, including Aβ accumulation and neuronal cell death, which could also be detected in BOs with familial APPSwe/Idl mutations, indicating that dysregulation of BACE2-mediated APP cleavage represents a possible pathogenesis mechanism of AD (Fig. 5).