Reversal of calcium dysregulation and related AD pathology with RyR negative allosteric modulators has been demonstrated in two PS1/APP lines (APPSWE/PS1M146V, 59; C57BL/6-SJLF1-APP+/−/C57BL/6-D2F1-PS1+/−; 113), Tg2576 [114], and PS1M146VKI mice [17]; and the restoration of normal Ca2+ signaling results in reduced amyloid and tau pathology, normalized synaptic transmission and plasticity, and improved cognitive function [59, 113, 114, 116, 117]. Here, PSEN1 is linked to Alzheimer disease.