We unveiled a molecular link between SMPD3 deficiency in the SM cycle of the neuronal Golgi complex, impeded remodeling of the lipid bilayer of the Golgi membrane, essential for budding, vesicle formation and protein transport of APP, Aβ and pTau, dysproteostasis, causing neurodegeneration and AD—like cognitive decline. This evidence concerns the gene APP and Alzheimer disease.