PSEN1 and Alzheimer disease: Indeed, our data could reconcile these two seemingly exclusive hypotheses on the effects of FAD mutations in PSEN1 on the development of AD by noting that: (1) there is a mutation-driven enhanced generation of Aβ42 within the endolysosomal network; (2) that through both endosomal production and endocytosis Aβ42 increases to a level within the endolysosomal network sufficient to inhibit the γ-secretase complex; and (3) that in the case of FAD mutations the isolation of the γ-secretase releases Aβ42, thus restoring wild-type enzyme activity (Veugelen et al., 2016; Shen and Kelleher, 2007).