Knockdown of ASM by siRNA in PS1 AD neurons normalized the levels of LC3-II, p62, LAMP1, and TFEB comparable to control neurons, reduced autophagosome number detected by EM, and further partially restored the impaired expression of TFEB target genes such as cathepsin B. These findings argue for a defect in autophagosomal-lysosomal fusion mediated by ASM activity in PS1 AD neurons. The gene discussed is PSEN1; the disease is Alzheimer disease.