How NSAIDs Work
As a class, non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs worldwide. They act by inhibiting cyclooxygenases, the enzymes that control the formation of prostaglandins which are significantly increased in inflamed tissue and contribute to the development of the cardinal subjective signs of acute inflammation -- fever and diffuse pain.
There are two subtypes of cyclooxygenases, COX-1 which is responsible for the baseline levels of prostaglandins, and COX-2 which is responsible for the massively increased production of prostaglandins during inflammation. This led to the development and launch of selective COX-2 inhibitors (the coxib class of drugs), however, these increase the risk of heart attacks in predisposed people and were removed from the market.
More Than Just COX Inhibitors
Cyclooxygenase inhibition is an incomplete explanation for the actions of NSAIDs, which act on additional inflammation mediating targets directly and indirectly (for example, see this review) The cytokine interleukin-6 is such an additional indirect target especially for neuroinflammation, on which few NSAIDs act. It is known to induce Alzheimer-type phosphorylation of tau protein by deregulating certain kinase pathways. It has been shown on many occasions that selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration.
NSAIDs Should Work in Alzheimer's, But...
Retrospective epidemiological meta-analyses have suggested for a long time that sustained intake of NSAIDs reduces the risk and delay the onset of Alzheimer's disease. In contrast, large therapeutic studies with NSAIDs in patients with established disease have not yielded positive results. Much less systematic work has been done to establish efficacy of NSAIDs in prevention of Alzheimer's disease, and much of the limited evidence obtained from studying trivial NSAIDs such as aspirin or naproxen has been negative or equivocal.
Could it be that something was overlooked?