February 8, 2000
A low-dose regimen of the steroid prednisone, an anti-inflammatory drug, is not effective in the treatment of Alzheimer's disease (AD), according to findings from a new clinical trial. The report, one of the first from a number of clinical trials trying to determine the usefulness of anti-inflammatory agents to prevent or treat AD, suggests that not all classes of such drugs may slow the rate at which people develop the disease or suffer cognitive decline.
The prednisone study, by investigators in the nationwide Alzheimer's Disease Cooperative Study (ADCS), appears in the Feb. 8, 2000, issue of the journal Neurology. Paul S. Aisen, M.D., of Georgetown University, was the principal investigator. The ADCS is directed by Leon Thal, M.D., at the University of California at San Diego.
In a related research development, the National Institute on Aging (NIA), which funded the prednisone study and supports the ADCS, announced the start of a multi-site clinical trial to examine another class of anti-inflammatory medications, NSAIDs, or non-steroidal anti-inflammatory drugs. This new trial will continue to follow up on epidemiological studies showing that people who take anti-inflammatory agents for medical problems are at lower risk for Alzheimer's disease and on basic research indicating that inflammation plays a major role in the AD disease process. Aisen is principal investigator of the new NSAIDs study as well.
The report on prednisone is an important step in directing scientists toward what works -- and what may not -- at certain stages of AD, notes Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch of the NIA's Neuroscience and Neuropsyhology of Aging Program. "Clinical trials such as this are critically important for following up on clues from basic and epidemiological research," says Buckholtz. "In this case, the trial suggests we need to examine carefully which drugs, or classes of drugs, work at various points in the development or progression of Alzheimer's disease. Compounds that may be useful at one stage or one dose may not be effective at another."
At its start, the prednisone study enlisted 138 people age 50 and older with probable AD. Half the participants were given a placebo and the other half prednisone in an initial dose of 20 mg (milligrams) daily for 4 weeks, lowered to a maintenance dose of 10 mg daily for one year, followed by a gradual tapering off of the drug for another 4 months. Cognitive and behavioral assessments were done at specific intervals over a 16-month period. Safety tests were also performed regularly throughout the study to monitor how participants tolerated the regimen.
The researchers looked for changes over a one-year period in the cognitive performance and behavior of study participants as determined by a cognitive component of the Alzheimer's Disease Assessment Scale (ADAS) and other tests. Overall, the testing showed that low-dose prednisone did not slow the rate of cognitive decline when those taking the drug were compared with those on placebo. The behavioral measures showed a significant decline among participants on prednisone; some 46 percent of those in the treatment group showed moderate to severe problems compared to 35 percent in the placebo group.
Aisen and colleagues suggest two major reasons why prednisone may not have been successful in treating AD. "I suspect the low dose was an important factor in the failure to see an effect," he explained. He and the study authors point out that much higher doses of prednisone have been used with success to treat other inflammatory diseases of the brain, but not over prolonged periods and not for elderly patients. Studies have indicated that higher doses of prednisone for a relatively long period of time are linked with serious toxicity in some older people. Adverse effects were seen in this study as well, indicating that higher, prolonged doses might cause substantial health risk.
Prednisone is a glucocorticoid, a particular class of anti-inflammatory and immunosuppressive agents. Glucocorticoids have a broad activity that, at the prednisone study's inception several years ago, was believed might have some benefit in treating AD. The prednisone and matching placebo were provided by Pharmacia & Upjohn.
Since then, however, other anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors, have become more available. Recent studies suggest that COX-2 inhibitors could act selectively as neuroprotective agents. Further, other anti-inflammatory agents, such as naproxen, specifically have been linked in epidemiological studies with decreased risk of AD. "The prednisone study is not a refutation of the potential benefit of anti-inflammatories," Aisen says. "It suggests that our testing of other agents, like certain NSAIDs, will be critically important in finding the right combination of therapies for AD." The new clinical trial announced today will test the efficacy of either naproxen or a COX-2 inhibitor in slowing AD progression. Bayer Corp. is providing the naproxen to be used in the upcoming study.
Clinical trials on AD are part of the NIA's Alzheimer's Disease Prevention Initiative, a national program aimed at finding ways to treat, and ultimately prevent, the neurodegenerative disease. NIA, one of 25 institutes and centers at the National Institutes of Health, leads the Federal effort in studying Alzheimer's disease, supporting basic, clinical, epidemiological, and social research on aging and the special needs of older people.
For specific information on Alzheimer's disease and clinical trials in progress, the public is urged to contact the NIA's Alzheimer's Disease Education and Referral Center (ADEAR) at 1-800-438-4380 or adear@alzheimers.org. You can visit the ADEAR website at www.alzheimers.org.
