PS1 mutants have also been shown to interact with ryanodine receptors and increase their activity (Rybalchenko et al., 2008; Chakroborty et al., 2009; Modesti et al., 2021), which combined with increased release from IP3-sensitive Ca2+ stores might contribute to elevated cytosolic Ca2+, excessive mitochondrial Ca2+ load, and Ca2+ dysregulation associated with AD (Figure 3). Here, PSEN1 is linked to Alzheimer disease.