Neuronal dysfunction is a common feature and final cause of death in Niemann-Pick Type C (NPC) disease, a rare storage disorder characterized by the accumulation of cholesterol and other lipids in the endosomal-lysosomal systems. Accumulating evidence indicates that NPC may share some common pathological mechanisms with Alzheimer’s disease (AD), and this includes the link between cholesterol and amyloid-β (Aβ). However, the mechanisms underlying neurodegeneration in NPC is unclear. Apolipoprotein E (apoE) plays pivotal role in cholesterol and lipid metabolism, and its polymorphism was found to modulate the susceptibility to develop AD. Like other cellular proteins, apoE undergoes post-translational modifications including glycosylation. Earlier studies have shown that apoE is differentially sialylated, but the functional significance of this chemical alteration and its association with Aβ pathology is unclear. In this study, we used an animal model of NPC to examine the glycan profile of apoE and its association with Aβ deposition and cholesterol metabolism at different stages of disease development.