In this study, we found that RyR2 destabilization due to CaM dissociation plays an essential role in the decrease in ER Ca2+ content, increase in ER stress and p-TAU, subsequently leading to neuronal cell loss and cognitive dysfunction in AppNL-G-F mice, and that either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) inhibition of CaM dissociation from RyR2 protected from AD (Supplementary Fig. 8). Here, RYR2 is linked to Alzheimer disease.