Previous studies suggested that the cellular prion protein (PrP^c) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Specifically, amyloid-β (Aβ) oligomers were proposed to cause synaptic and cognitive dysfunction by binding to PrP^c. To test this hypothesis, we crossed human amyloid precursor protein (hAPP) transgenic mice from line J20 onto a PrP^c-deficient background. Ablation of PrP^c did not prevent the premature mortality and abnormal neural network activity typically seen in hAPPJ20 mice. Furthermore, hAPPJ20 mice with or without PrP^c expression showed comparably robust abnormalities in learning and memory and in other behavioral domains at 6–8 months of age. Notably, these abnormalities are not refractory to therapeutic manipulations in general: they can be effectively prevented by interventions that prevent Aβ-dependent neuronal dysfunction also in other lines of hAPP transgenic mice. Thus, at least in this model, PrP^c is not an important mediator of Aβ-induced neurological impairments.