Despite the initial activation of IRE1 signaling that may decrease the accumulation of abnormal proteins in AD, the continuous activation of IRE1 would mediate the phosphorylation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and the inhibition of XBP1 splicing, which can trigger the c-Jun NH2-terminal kinase (JNK) signaling pathway and cause neuronal apoptosis [55,56]. This evidence concerns the gene ERN1 and Alzheimer disease.