Accumulating research supports the neuroprotective effects of pomegranate (Punica granatum) juice and extracts against Alzheimer's disease (AD) but there is limited data available in animal models. Here we investigated the effects of a standardized pomegranate extract (PE) on AD pathology in an aged transgenic AD animal model (R1.40).The mice (age 24-30 months) received either PE (at 100 and 200 mg/kg) or a control solution daily for three weeks, and were evaluated in the Morris water maze and the Y-maze for improvements in spatial long-term and working memory functions. Cortical amyloid-β precursor protein (APP) and amyloid-β (Aβ) levels, along with other relevant biomarkers for AD, were measured in brain tissues. PE did not improve cognitive performance of the mice, but altered levels and ratio of the Aβ42 and Aβ40 peptides which would favor a diminution in AD pathogenesis. Further analysis revealed that this reversal could be the product of the modification of γ-secretase enzyme activity, the enzyme involved in the generation of these Aβ isoforms. Our findings support a specific anti-amyloidogenic mechanism of a pomegranate extract in this aged AD animal model.