The overall aim of this investigation was to study the effects of a commonly used statin , simvastatin, on learning and memory in the Tg 2576 transgenic mouse model of AD, and non transgenic littermates. Simvastatin reduced plasma lipoprotein cholesterol levels with out hepatic toxicity. Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. However, Simvastatin treatment had no significant effect on the steady-state levels and depositions of β-amyloid in the brain of Tg mice. Simvastatin treatment did not affect the steady-state levels of cholesterol and apolipoprotein E in brain. Simvastatin treatment was associated with increased expression levels of signal transduction pathways e.g., protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS), in mouse brain. In conclusion, this study showed that simvastatin treatment reversed learning and memory deficits in Tg2576 mice independent of cerebral Aβ levels and enhanced cognitive function in normal-aged non-Tg mice, and suggest that simvastatin may exert its beneficial effects directly through modulation of signaling pathways in memory formation independent CNS beta amyloid levels.