Background It was reported that amyloid precursor-like protein 2 (APLP2) increases PCSK9-mediated low-density lipoprotein receptor (LDLR) degradation, and sortilin facilitates PCSK9 secretion. Results APLP2 or sortilin deficiency/overexpression in cells/mice did not affect LDLR degradation by PCSK9. However, APLP2 binds sortilin, and PCSK9 enhances their degradation. Conclusion APLP2/sortilin are not required for PCSK9 activity on LDLR, but their interaction may modulate APLP2 functions. Significance APLP2 and sortilin do not affect LDLR levels.