Here, we tested the hypothesis that depleting rat primary cortical neurons of PI(3,5)P2, the TRPML1 agonist, by inhibiting PIKfyve kinase activity using the pharmacological inhibitor YM201636, would recreate the key EAL defects we detected in AD brain and in human neuronal APOE ε4 iPSCs. Here, APOE is linked to Alzheimer disease.