Although it is possible that familial AD (fAD) mutations in PS1 [23] or recruitment of Aph1B isoform [38] produce more stable γ-secretase complexes with PS1 in pathogenic “closed” conformation, our current study shows that allosteric changes in the pre-existing γ-secretase complexes can occur in response to Ca2+. Here, APH1B is linked to familial Alzheimer disease.