APP and early-onset autosomal dominant Alzheimer disease: As mentioned above and discussed in detail below (see Section 25), in Alzheimer’s disease AβPP-derived iAβ, accumulated over the critical threshold, elicits the neuronal ISR and thus activates the AβPP-independent production of C99, and, as presumed in this iteration of the ACH2.0, of iAβ that drives the disease.