We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity.<h4>Methods</h4>To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. This evidence concerns the gene SMPD3 and Alzheimer disease.