The pathological endolysosomal enlargement evident in AD neurons, which is also apparent in APOE ε4-expressing cells (Nuriel et al., 2017; Xian et al., 2018), coupled with the disruption of TRPML1-mediated Ca2+ efflux that we describe here for the first time, supports the idea that there is an inability to effectively regulate lysosomal fusion–fission cycles, which are essential for regulation of lysosome number, size and function, in AD (Bissig et al., 2017; Li et al., 2016; Saffi and Botelho, 2019). This evidence concerns the gene MCOLN1 and Alzheimer disease.