Decades of research indicate that calcium dysregulation is an early driver of AD pathology in both sporadic and autosomal dominant disease (Alzheimer’s Association Calcium Hypothesis, 2017; Gant et al., 2018; Khachaturian, 1994), with elevated calcium in the cytosol, rather than stored in the SER, activating calpain-2 to disinhibit GSK3β and cdk5 to hyperphosphorylate tau (Arnsten et al., 2021b; Arnsten et al., 2021c). Here, CDK5 is linked to autosomal dominant disease.