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A Boost for NSAIDs in Alzheimer's Prevention

Two studies suggest that Alzheimer's disease may be prevented with NSAIDs - and that future drug development may optimize the AD-preventive aspects of NSAIDs.

These two studies move the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing Alzheimer's disease (AD) to top priority for large-scale, well-controlled, prospective trials.

In the study by in 't Veld and colleagues, the researchers prospectively followed a population-based cohort of 6989 initially nondemented Dutch individuals (minimum age, 55) for up to 8 years. The researchers tracked the subjects' cognitive status and reviewed computerized pharmacy records for use of NSAIDs (which were prescription-only in the Netherlands until 1995). Subjects who had used NSAIDs cumulatively for at least 24 months showed a robustly lower relative risk for AD compared with those who had used NSAIDs for shorter periods or not at all; the RR for AD after long-term NSAID use was 0.20 compared with no NSAID use. NSAID use was not associated with lower risk for vascular dementia, thereby demonstrating the specificity of the effect.

The study by Weggen and colleagues places these clinical findings on firm experimental ground. A subset of NSAIDs applied to cultured cells and to a mouse model of AD preferentially decreased levels of Aß42, the more toxic form of the Aß peptide. Perhaps the most interesting finding was a concomitant increase of a shorter Aß fragment, Aß38. As the authors note, these effects contrast favorably with those of -secretase inhibitors, compounds that affect the generation of all -secretase substrates and, as such, are likely toxic. Curiously, the third most commonly prescribed NSAID in the clinical study, naproxen, did not have an effect in the cultured cells.

Comment: Although these studies will no doubt spur additional research, neither yet offers the clinician a clear direction for new treatment options. Many questions must be answered before the most effective NSAID -- and its optimal dose -- can be determined. Furthermore, whereas presenilin mutations unfavorably shift the substrate specificity of the -secretase, NSAIDs appear to shift the substrate specificity favorably along the intramembranous -helical face of the amyloid precursor protein. Optimizing this mechanism of action seems a promising strategy for the development of next-generation compounds for AD prevention.

— Kenneth S. Kosik, MD

Dr. Kosik is Professor of Neurology, Center for Neurologic Disease, Brigham and Women's Hospital, Boston.

Published in Journal Watch Neurology March 28, 2002

Citation(s):

in 't Veld BA et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001 Nov 22; 345:1515-21.

• Original article (Subscription may be required)
• Medline abstract (Free)

Weggen S et al. A subset of NSAIDs lower amyloidogenic Aß42 independently of cyclooxygenase activity. Nature 2001 Nov 8; 414:212-6.

• Medline abstract (Free)