APP and early-onset autosomal dominant Alzheimer disease: But, in humans, it is the beginning of another story: the same neuronal ISR that suppresses the production of AβPP-derived Aβ (and, by extension, of AβPP-derived iAβ) activates and enables the operation of and sustains the AβPP-independent pathway of the generation of the C100/C99 fragment of AβPP, the pathway, which drives Alzheimer’s disease.