Selegiline (or Eldepryl) and alpha-tocopherol (or Vitamin E) may slow important functional signs and symptoms of Alzheimer's disease by about 7 months, according to a report by scientists at 23 Alzheimer's Disease Cooperative Study (ADCS) sites across the U.S. The two drugs delayed important milestones, such as entry into nursing homes, for people with moderately severe Alzheimer's disease, and decreased their loss of daily activities, including bathing, dressing, and handling money, by about 25 percent.
Department of Health and Human Services Secretary Donna E. Shalala called the finding "very good news. Each piece of the Alzheimer's disease puzzle that falls into place moves us one step closer to relieving the burden of this devastating disease."
Findings from the study, the longest clinical trial to date testing drugs for slowing the progression of Alzheimer's disease, are reported in the April 24, 1997, The New England Journal of Medicine. Mary Sano, Ph.D., of Columbia University College of Physicians and Surgeons, principal investigator for this study, Leon J. Thal, M.D., University of California at San Diego, principal investigator of the ADCS, and colleagues reported the findings on behalf of scientists at the ADCS sites. The National Institute on Aging (NIA), part of the National Institutes of Health at the Department of Health and Human Services, funded this study as part of the ADCS, a consortium of 35 research centers.
"We looked at the signs and symptoms of Alzheimer's disease that can worsen over time and found that in patients taking these drugs, these signs occurred later," said Sano. "Physicians may want to think about using either selegiline or Vitamin E in patients with moderately severe disease, like those in our study. The drugs may benefit certain patients by delaying some aspects of the deterioration that comes with the disease. Of course, potential side effects and drug interactions need to be considered as well," she added.
Beyond their significance for today's patients, the findings are important in understanding the factors involved in the symptoms of Alzheimer's disease. Researchers exploring the idea that oxidative damage may play a role in Alzheimer's disease theorize that drugs such as selegiline and alpha-tocopherol keep oxidative damage of brain cells at bay, and therefore may be effective in reducing symptoms of the disease.
"This study reinforces the thinking that oxidative damage plays a role in Alzheimer's disease, and we are actively pursuing this line of research," says Neil Buckholtz, Ph.D., acting chief of the dementias of aging branch at the NIA. "Now that we have seen an effect in this group of patients, we will need to look further to determine whether these types of drugs can actually delay the development of symptoms much earlier in the course of the disease."
The clinical trial examined the effects of the two drugs in 341 patients. The participants were divided into four groups, including those receiving placebo, those receiving 10 milligrams of selegiline per day, those taking 2,000 IU (international units) of Vitamin E per day, or people taking a combination of both drugs. Both selegiline, a drug widely used to treat Parkinson's disease, and Vitamin E are currently available.
Using novel, more functional measures of the disease's progression than have been used to study the disease in the past, the researchers assessed the patients every 3 months for 2 years, marking four important milestones in the progression of the disease -- death, institutionalization, loss of the ability to perform basic daily activities, and progression to severe dementia.
The scientists found a significant delay after treatment with either drug, in an analysis that combined all four milestones. With selegiline, when compared to placebo, it took 215 days longer to reach any one of the four milestones. With Vitamin E, the delay was about 230 days. The combination of the drugs showed less of an effect, with a delay of only 145 days.
Looking at the milestones separately, the treatment groups did somewhat better in most categories compared with those receiving a placebo. The results were not statistically significant except for a 13 percent reduction in entry into a nursing home among people taking Vitamin E during the period of the study.
On one important, commonly used measure of function in everyday activities, the Blessed Dementia Scale, people in the three treatment groups showed about 25 percent less deterioration of abilities such as eating, dressing, or cooking than those not receiving the drug therapies.
While the measurements of the disease's progression in practical terms showed that the drugs were having a positive effect, there was no improvement in cognition. Measurements of cognition tested memory, attention, language, and comprehension. More research will be needed to see whether the positive findings on function were the result of other improvements in health, such as cardiovascular effects, that are associated with antioxidants, rather than being the direct consequence of antioxidant action on the brain. Two drugs already approved for treatment of Alzheimer's disease, tacrine and donepezil, have been shown to improve cognition by about 6 months. The demonstrated benefits of selegiline and Vitamin E on the functional milestones occurred over a 2-year period.
Scientists were surprised that people taking the combination of the drugs did not do as well or better than those taking either selegiline or Vitamin E separately. From laboratory studies, they had expected the drugs to have an additive effect, since each works in a different way to prevent oxidative damage. The unexpected results in humans highlights how important it is to do controlled clinical trials to test ideas from the laboratory, the researchers emphasized.
While heartened by the finding that either selegiline or Vitamin E moderates some of the signs of Alzheimer's disease, scientists still were cautious about recommending immediate, widespread application of either drug. First, they noted, the study involved patients with moderately severe disease, and more research needs to be conducted to see how the drugs might affect patients at different stages of the disease. Also, use of selegiline could be have potential side effects and interactions with other drugs. In addition, the dosage of Vitamin E used in this study was substantially higher than that typically taken by people as a daily vitamin supplement. Vitamin E may be associated with increased risk of bleeding in certain individuals. Alzheimer's disease patients and their families should consult their physicians on whether these drugs or tacrine (brand name Cognex) or donepezil (brand name Aricept) may be appropriate for a particular individual.
The study reflects progress in the ADCS, set up 6 years ago to facilitate research on treatments for Alzheimer's disease. "The study reported today highlights one important aspect of the program, testing drugs or substances that are already on the market but that may prove useful in delaying decline among Alzheimer's disease patients," Thal noted. Observational studies indicate that estrogen or anti-inflammatory agents, for example, may also have some positive benefits on Alzheimer's disease, Thal said, and scientists in the ADCS are testing these two substances and others in controlled trials to determine if they really do offer a benefit.
The NIA conducts research into the biomedical, clinical, social, and behavioral aspects of aging and the needs of older people. The Institute sponsors the Alzheimer's Disease Education and Referral Center (ADEAR), where the public and health professionals can obtain information on dementia. The ADEAR Center can be contacted at 1-800-438-4380.