We have discussed how dysregulated PERK signalling is detrimental to neuronal survival in the context of PrP, mutant tau and TDP-43 aggregation, and to learning and memory in both health and disease models, as well as the association of PERK-P and eIF2α-P with progression of Alzheimer’s disease. Here, TARDBP is linked to early-onset autosomal dominant Alzheimer disease.