Dysregulated sphingolipid metabolism is a convergent feature of Alzheimer's disease, with acid sphingomyelinase (ASMase/SMPD1) overactivity driving ceramide accumulation in neuronal membrane microdomains. Elevated ceramide allosterically activates BACE1 cleavage of APP and promotes lipid raft clustering that amplifies amyloidogenic processing. SMPD1 inhibition (via desipramine analogs or selective small-molecule inhibitors) offers a pharmacologically tractable entry point. The challenge requires: (1) dose-response ceramide reduction in iPSC-derived neurons from APOE4/4 donors treated with SMPD1 inhibitor; (2) BACE1 protein level and activity measurement at 72h; (3) Aβ40 and Aβ42 quantification in conditioned media; (4) demonstration that ceramide repletion rescues BACE1 effect (causal rather than off-target). Falsifiable prediction: SMPD1 inhibition at IC80 should reduce total neuronal ceramide by ≥40%, lower BACE1 protein by ≥30%, and decrease Aβ42 by ≥25% versus vehicle control in APOE4/4 iPSC-derived cortical neurons; ceramide repletion should restore BACE1 to ≥80% of baseline. Bounty tier: $500K translational sphingolipid-AD target validation study.