Neuroinflammation in Alzheimer's disease: are NSAIDs and selective COX-2 inhibitors the next line of therapy?

Alzheimer's disease (AD) is currently treated with cholinergic and glutamatergic therapies, which provide symptomatic benefit but do not reverse the underlying pathology or cognitive deficits. The prevalence of AD is expected to triple over the next 50 years, creating an urgency to develop effective "disease-modifying" therapies to reduce the economic burden of this devastating disorder. One of the main areas of therapeutic focus has been an antiinflammatory strategy based on an inflammatory hypothesis of AD. This hypothesis originated from epidemiological evidence that long-term exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) protected against the development of AD. However, large-scale double-blind placebo-controlled clinical trials have not supported the use of NSAIDS in treating AD. The following review outlines epidemiological, preclinical, and clinical evidence evaluating the efficacy of various NSAIDs and selective COX-2 inhibitors in AD. We also review recent anecdotal data with the TNF-α inhibitor, etanercept, and discuss possible explanations for the failure of preclinical data to translate into successful clinical trials.