Alzheimer's disease (AD) is a consequence of degenerative brain pathology with amyloid plaque deposition and neurofibrillary tangle formation. These distinct aspects of AD neuropathology have been suggested to induce a cascade of pathological events ultimately leading to neurodegeneration as well as cognitive and behavioral decline. Amyloid and tau neuropathology is known to develop along distinct stages and affect parts of the brain differentially. In this study, we examined two mouse AD lines (AβPPPS1-21 and Tau22 mice), which mimic different partial aspects of AD pathology, at comparable stages of their pathology. Since prefrontal cortex (PFC) is one of the first regions to be affected in clinical AD, we compared long-term potentiation (LTP) of synaptic responses in medial PFC of AβPPPS1-21 and Tau22 mice. Frontal LTP was impaired in AβPPPS1-21 mice, but not in Tau22 mice. Consequently, we observed different behavioral defects between AβPPPS1-21 and Tau22 animals. Apart from spatial learning deficits, AβPPPS1-21 transgenic mice were impaired in fear learning, aversion learning, and extinction learning, whereas THY-Tau22 were impaired in appetitive responding. Discriminant function analysis identified critical behavioral variables that differentiated AβPPPS1-21 and THY-Tau22 mice from wild type littermates, and further confirmed that amyloid- versus tau-pathology differentially affects brain function.