Damaging calpain overactivation has been associated with the pathogenic reduction of the natural endogenous calpain inhibitor calpastatin in vivo models of Alzheimer’s disease (Rao et al., 2014), amyotrophic lateral sclerosis (Rao et al., 2016) and Huntington’s disease (Hu et al., 2021). This evidence concerns the gene CAST and early-onset autosomal dominant Alzheimer disease.