Niemann-Pick type C disease (NPC) is a lysosomal storage disorder which, at the cellular level, shows amyloid Aβ and tau pathologies comparable to those seen in the AD brain. Here, we have investigated, in a mouse model of NPC, the impact of removing the source of Aβ, namely APP, on the disease phenotype and on the expression levels and phosphorylation patterns of tau. We reasoned that removing APP from the NPC brain might help to unveil its impact on the disease phenotype and shed light on the mechanisms governing the interaction, both physiological and pathological, between APP function and tau homeostasis, at least in NPC. We show that, unexpectedly, loss of APP in NPC mice leads to poorer neuromuscular coordination and cumulative survival rates; exacerbation of their cholesterol abnormalities; higher levels of astrocytosis and dysregulation of tau homeostasis. Our results are consistent with a mechanism of neurodegeneration in the NPC and AD brains in which cholesterol dysregulation is a key early pathogenic event affecting tau homeostasis in parallel with, and independently of, amyloid accumulation.