Accordingly, it was also reported that the RyR agonist caffeine evoked larger Ca2+ liberation in primary cultured neurons derived from the triple transgenic mice model 3xTg-AD (knock in for the mutated PS1M146V, and overexpressing mutated βAPP and microtubule-associated tau protein (PS1M146V/APPswe/tauP30IL)), and the transgenic knock in mice model expressing mutated PS1 (PS1M146V)[94]. Here, RYR1 is linked to Alzheimer disease.