This in vivo finding and our in vitro observations that calreticulin binds to APP, Aβ40 and Aβ42, presenilin and nicastrin and that it reduces the production of Aβ40 and Aβ42 provide strong evidence that calreticulin regulates the γ-secretase-mediated processing of APP in vivo, raising the possibility that calreticulin may be a target in preventing an important aspect of AD pathology. Here, NCSTN is linked to Alzheimer disease.