APPS198P segregates with rare familial forms of Alzheimer’s disease and resides within exon 5, unlike 27 other mutations that reside in exons 16 or 17. In this issue, Zhang et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210313 ) show that the brains of APPS198P transgenic mice accumulate excess levels of Aβ. In cultured cells, APPS198P undergoes accelerated ER folding, leading to early arrival in late vesicular compartments, thereby enhancing generation of Aβ.