The study investigated effects of gamma secretase modulator R-flurbiprofen on AD neuropathology in 3xTg-AD mice. Multiple epidemiological studies have shown that treatment with NSAIDs was associated with a reduced risk of developing AD. However, the results of pharmacological studies with anti-inflammatory agents have been inconsistent in both mice and humans. Interest in the effects of NSAIDs on AD grew faster after a subset of NSAIDs was found to decrease the production of the more amyloidogenic Aß42 peptide at the expense of shorter and less toxic Aß forms, which appears to involve the allosteric modulation of γ-secretase. Treatment with R-flurbiprofen, an enantiomer of flurbiprofen that maintains the GSM activity in vitro and in vivo, but lacks antiinflammatory activity, attenuated learning impairments and lowered Aß42 in vivo. In this study, treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau. No significant changes in the level of Aß were detected. Using magnetic resonance spectroscopy (MRS), R-flurbiprofen decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. There was an inverse correlation between the concentration of glutamate and learning across all the mice in the study. This study suggests that glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function.