The protein kinase and endoribonuclease IRE1 could have a role in Alzheimer disease (AD) pathogenesis, according to new research. Activation of IRE1 was associated with more-advanced AD pathology in human post-mortem brain. In addition, ablation of the RNase domain of IRE1 in a mouse model of AD reduced amyloid plaque burden and astrocyte activation, and ameliorated learning and memory deficits in the animals. The team also found that inhibition of signalling downstream of IRE1 in cultured cells resulted in retention of amyloid precursor protein (APP) within the endoplasmic reticulum, with subsequent degradation of APP at the proteasome. These results suggest that IRE1 represents a novel target for therapy in AD.