A good number of pharmacologic agents have over the years been touted as potentially beneficial in either preventing the onset or delay the progression of Alzheimer's disease. These include compounds such as non-steroidal anti-inflammatory drugs (NSAIDs) (HMG-CoA reductase inhibitors (statins)) and flavonoids. The underlying mechanisms for the beneficial effect of these agents are by and large attributed to their ability to reduce beta-amyloid (Abeta) production and amyloid load in the brain, via inhibition of amyloidogenic gamma-secretase activity. Recent reports have now provided mechanistic insights as to how non-amyloidogenic processing might also be enhanced by these seemingly unrelated treatments. Intriguingly, this appears to involve the inhibition of the activity of small GTPase Rho and its effector, the Rho-associated kinase, ROCK. Dietary caloric restriction (CR) also enhances non-amyloidogenic processing of APP, and this may be part of a more general anti-aging effect of CR mediated by gene expression changes downstream of the activity of the histone deacetylase SIRT1.