Here, we found that in HEK293 cells stably expressing APOE proteins, that APOE4 expression stimulates macroautophagy but may ultimately reduce autophagic flux, and that this protein accumulates in enlarged lysosomes with altered proteomic contents compared to what is seen with APOE3, suggesting a possible contributing mechanism to loss of proteostasis observed in AD. This evidence concerns the gene APOE and Alzheimer disease.