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How Anti-Inflammatory Drugs Help in Alzheimer’s, If They Do
  
By Edward R. Winstead

Alzheimer's Drugs?Drugs used to treat inflammation, such as ibuprofen and indomethacin, may offer some protection against Alzheimer's disease by reducing the protein fragments that accumulate in the brain.

The jury is still out on whether non-steroidal anti-inflammatory drugs should be prescribed for Alzheimer's patients (a recent clinical trial involving two anti-inflammatories found no benefit), but researchers are investigating the mechanisms by which the drugs may help.

In a new study, researchers suggest that some anti-inflammatories reduce the levels of a protein fragment (or peptide) associated with Alzheimer's by interfering with two proteins that help manufacture the fragment in the first place. The proteins are called Rho and Rock.

The researchers inhibited Rho and Rock in mutant mice and significantly reduced the levels of the most dangerous peptide found in humans, called amyloid-ß-42. Amyloid peptides form the plaques that are a signature of Alzheimer's disease. The findings are reported in Science.

“The take-home message from this study is that if non-steroidal anti-inflammatory drugs are effective, they may be effective through this [Rho-Rock] mechanism,” says Steven M. Paul of Lilly Research Laboratories in Indianapolis, who led the study. “The mechanism may be unrelated to what these drugs do as anti-inflammatories.”

By understanding the effects of anti-inflammatories on peptides, researchers could in theory design drugs that target the underlying biology of Alzheimer's.

Not all anti-inflammatory drugs will be protective or reduce the risk of Alzheimer's. --Steven M. Paul“Not all anti-inflammatory drugs will be protective or reduce the risk of Alzheimer's,” says Paul, who with his colleagues is trying to figure out the mechanism by which amyloid plaques form.

Anti-inflammatory drugs have already been tested, without success, in Alzheimer's patients. This summer, researchers cut short a multi-center clinical trail funded by the US National Institutes of Health to test two anti-inflammatory drugs, Aleve and Vioxx, in Alzheimer's patients because the drugs had no clear effect on the disease. Aleve (also called naproxen) is a non-steroidal anti-inflammatory used to treat pain and swelling; Vioxx (also called rofecoxib) is a COX-2 inhibitor used to treat pain and osteoarthritis.

“These drugs do not slow the cognitive decline in patients with mild-to-moderate Alzheimer's disease,” concluded Paul Aisen of Georgetown University Medical Center in Washington , D.C. Aisen and his colleagues reported the disappointing findings in the Journal of the American Medical Association in June.

Still, the matter is hardly resolved. In July, researchers reported that non-steroidal anti-inflammatory drugs “offer some protection against the development of Alzheimer's disease.” This conclusion was based on data from 9 studies (published between 1966 and 2002) that explored the risk of Alzheimer's disease among people who used this class of drugs, including aspirin.

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Specifically, the researchers found that the use of non-steroidal anti-inflammatory drugs seems to lower the risk of developing Alzheimer's in adults younger than age 55. The findings, by Mahyar Etminan, an epidemiologist at Royal Victoria Hospital in Quebec, and two colleagues appeared in the British Medical Journal.

In August, the same journal published a commentary that discussed the new analysis in light of the discouraging results of the randomized clinical trial involving Aleve and Vioxx. The author, Christopher Martyn of the Southampton General Hospital, the U.K., noted that Paul's group may have tested the wrong anti-inflammatories for a population in the early stages of Alzheimer's.

Likewise, he said, it's possible that the protective effect suggested by the observational studies may not have taken into account important factors that had nothing to do with the effects of anti-inflammatory drugs. For instance, people who take anti-inflammatories may be genetically predisposed to not getting Alzheimer's, or may live their lives in ways that reduce their likelihood of developing the disease.

Despite what we would like to believe, Martyn concludes, the evidence implying that these drugs protect against Alzheimer's is still tentative.

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Zhou, Y. et al. Nonsteroidal Anti-Inflammatory Drugs Can Lower Amyloidogenic Aβ42 by Inhibiting Rho. Science 302, 1215-1217 (November 14, 2003).

 

Etminan, M. et al. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ 327, 128-132 (July 19, 2003).

 

Martyn, C. Anti-inflammatory drugs and Alzheimer's disease. BMJ 327, 353-354 (August 16, 2003).

 

Aisen, P.S. et al. Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819-2826 (June 4, 2003).

 

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