Is it best to keep NSAIDs away from microglia (shown here)? Credit: Butovsky, O. et al. PNAS

Hope that the readily available drugs celecoxib and naproxen might prevent Alzheimer's disease took a blow with the recent release of data from a large randomized trial1. In contrast to results expected from epidemiological studies, the report found that the drugs did not improve cognitive function in elderly individuals with a family history of Alzheimer's disease. What's more, the study suggests that naproxen may even be detrimental. Do the findings sound the death knell for the experimental approach of treating Alzheimer's disease with nonsteroidal anti-inflammatory drugs (NSAIDs)?

Colin Masters:

It's not a good idea to try to impair the natural healing response of the brain. CM

For a long time now, there has been retrospective evidence that anti-inflammatories might have some protective effects in Alzheimer's disease, but this prospective study clearly shows that such evidence is incorrect. These results are not surprising, as we know that Alzheimer's disease is not caused by inflammatory processes. Indeed, the exact opposite seems to be true—the microglia in the brains of individuals with the disease are probably beneficial in the brain's response to the deposition of neurotoxic β-amyloid, a hallmark of the disease. This notion is supported by the present study, in which a slight adverse impact of the drugs was seen, indicating that it is not a good idea to try to impair the natural healing response of the brain.

Executive Director, Mental Health Research Institute, University of Melbourne, Parkville, Australia.

Tony Wyss-Coray:

Many arguments can be made as to why this first primary prevention trial testing two different NSAIDs, similar to previous treatment trials, showed no benefit at all: the choice of NSAIDs, the duration of treatment, or the advanced age or presymptomatic neurodegeneration in the subject population. But maybe we must look elsewhere.

Yet another long-term longitudinal study, this one of a quarter-million veterans, recently concluded that long-term use of certain NSAIDs can reduce the risk of Alzheimer's disease by almost half2. One fundamental difference between these two types of studies is that NSAID prescription is probably triggered by an inflammatory disease in epidemiological settings, whereas the current prevention trial and previous treatment studies select subjects without 'confounding' chronic inflammatory diseases.

Is it therefore possible that systemic inflammatory conditions, alone or in combination with NSAIDs, protect against Alzheimer's disease?

Associate Professor, Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.

Giulio Maria Pasinetti:

This study adds to the negative evidence from treatment trials suggesting that NSAIDs do not counteract Alzheimer's disease—including a recent study that examined an NSAID derivative known to weakly lower β-amyloid abundance in the brain in preclinical studies ( More translational research is needed, including work examining why individuals treated with certain NSAIDs have increased risk of thromboembolic events and ischemic stroke, and pharmacogenomic investigations of polymorphic genes that may influence the turnover and bioavailablity of NSAIDs. Such research, and the clarification of how NSAIDs mechanistically influence Alzheimer's disease, is mandatory before NSAIDs can be used for the prevention or treatment of the disease.

Director, Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer's Disease, Mount Sinai School of Medicine, New York, New York, USA.