The medial temporal lobe-dependent memory loss associated with Alzheimer’s disease (AD) is often accompanied by a loss of prefrontal cortex-dependent cognitive domains that fall under the broad category of executive function. In this study, we examined the relationship between one type of prefrontal-dependent executive function, discrimination reversal learning, and levels of the amyloid beta protein (Aβ) of 40 and 42 residues in a transgenic mouse model (Tg2576) of the over-expression of the familial AD mutant form of the amyloid precursor protein (APPsw). Tg2576 and their non-transgenic (NTg) littermates were assessed at 3 and 6 months of age when there is little to no amyloid plaque deposition. After reversal learning assessment, Aβ40 and Aβ42 were quantified in the prefrontal cortex and hippocampus. Tg2576 mice were impaired in reversal learning at 6 but not 3 months of age when compared to the NTg group. Coincidently, there was a corresponding approximately 3-fold increase of Aβ42 levels in the prefrontal cortex of 6- compared to 3-month-old Tg2576 mice. In addition, the prefrontal cortex contained higher levels of Aβ42 compared to the hippocampus at both 3 and 6 months of age, regardless of genotype, indicating a high vulnerability of this brain region to Aβ42 accumulation. These data suggest that the early emergence of reversal learning deficits in the Tg2576 mouse may be due to the localized increase of Aβ42 in the prefrontal cortex.