New Drug Therapies Delay Effects of Alzheimer's Disease

National Institute AgingFOR RELEASE, Wednesday, Apr. 23, 1997, Vicky Cahan/Claudie Feldman, NIA, Elaine Metcalf, Columbia Univ.

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 or by e-mail at adear@alzheimers.org. ADEAR's website is located at .

Questions and answers about the study and a list of the research sites is attached.

Video b-roll is available.

Sites Participating in Selegiline and Vitamin E Protocol

Robert E. Becker, M.D. Southern Illinois University Alzheimer's Disease Research Prg Po Box 19230 1412 Springfield, Il 62794 (217) 785-4468 (217) 524-2275 Fax

Jeffrey Kaye, M.D. Oregon Health Sciences Univ. Dept. Of Neurology Cdw2 3181 Sw Sam Jackson Park Rd. Portland, or 97201 (503) 494-6976 (503) 494-7499 Fax

Lon S. Schneider, M.D. Univ. Of Southern California School of Medicine 2011 Zonal Avenue Hmr101 Los Angeles, ca 90033 (213) 342-3715 (213) 342-3717 Fax

John Growdon, M.D. Massachusetts General Dept. Of Neurology Acc 830 15 Parkman Street Boston, Ma 02114 (617) 726-1728 (617) 726-4101 Fax

Leon J. Thal, M.D. Univ. Of California, San Diego Department of Neurology 0624 9500 Gilman Dr. La Jolla, ca 92093 0624 (619) 552-8585 X3685 (619) 534-2985 Fax

Norman Foster, M.D. University of Michigan 1920/0316 Taubman Center 1500 E Medical Center Drive Ann Arbor, Mi 48109 0316 (313) 936-9045 (313) 936-8763 Fax

Ronald C. Petersen, Md., Ph.d. Mayo Clinc Department of Neurology 200 First Street Sw Rochester, Mn 55905 (507) 284-4006 (507) 266-4752 Fax

Murray Raskind, M.D. University of Washington Va Puget Sound Healthcare Department of Psychiatry (116a) 1660 S. Columbian Way Seattle, Wa 98195 (206) 764-2063 (206) 764-2573 Fax

Rachelle S. Doody, M.D., Ph.d. Baylor College of Medicine Department of Neurology 6550 Fannin, Suite 1801 Houston, Tx 77030 (713) 798-7416 (713) 798-5326 Fax

Mary Sano, Ph.d. Columbia University Sergievsky Center P&s Bldg, Box 16 630 West 168th Street New York, Ny 10032 (212) 305-9194 (212) 305-2426 Fax

John C Morris, M.D. Washington University Memory Diagnostic Center Barnes Jewish Hospital 4932 Forest Park Blvd., Ste. 6c St Louis, Mo 63108 (314) 454-4506 (314) 454-5605 Fax

Lindy Harrell, M.D., Ph.d. University of Alabama Birmingham Sparks Building Suite 454 1720 7th Avenue South Birmingham, Al 35294 (205) 934-3847 (205) 975-7365 Fax

Kenneth L. Davis, M.D. Mt. Sinai School of Medicine Department of Psychiatry One Gustave Levy Place, Box 1230 New York, Ny 10029 (212) 824-7008 (212) 860-3945 Fax

David Bennett, M.D. Rush Presbyterian St. Lukes Medical Center Alzheimer's Disease Center 1645 W. Jackson Suite 675 Chicago, Il 60612 (312) 942-3350 (312) 942-2861 Fax

David Knopman, M.D. University of Minnesota University of Minnesota Hospital Department of Neurology, Box 295 Minneapolis, Mn 55455 (612) 625-9900 (612) 625-7950 Fax

Carl Eisdorfer, M.D. University of Miami Dept. Of Psychiatry & Behavioral Sciences 1425 Nw 10th Avenue, Room 205 Miami, Fl 33136 (305) 243-4782 (305) 243-6726 Fax

David S. Geldmacher, M.D. University Hospitals Of Cleveland Alzheimer's Center 11100 Euclid Ave. Cleveland, Oh 44106 (216) 844-8203 (216) 844-7239 Fax

Claudia Kawas, M.D. Johns Hopkins University Bayview Medical Center 5501 Hopkins Bayview Circle Room 1b 82 Baltimore, Md 21224 (410) 550-3365 (410) 550-3364 Fax

Eric Pfeiffer, M.D. University of South Florida Health Sciences Center 12901 Bruce B. Downs Blvd., Mdc Box 50 Tampa, Fl 33612 (813) 974-4355 (813) 974-4251 Fax

Steven H. Ferris, Ph.d. New York Univ. Medical Center Aging & Dementia Research Center 550 First Avenue, Room Thn 312b Nyc, Ny 10016 (212) 263-5703 (212) 263-6991 Fax

Warren Strittmatter, M.D. Bryan Alzheimer's Disease Research Center Memory Disorder Clinic 725 Broad Street Durham, Nc 27705 (919) 684-6274 (919) 684-6514 Fax

Christopher M. Clark, M.D. University of Pennsylvania Dept. Of Neurology Memory Disorder Clinic 3 West Gate 3400, Spruce Street Philadelphia, Pa 19104 (215) 622-7810 (215) 662-7812 Fax

Frederick Schmitt, Ph.d. University of Kentucky Sanders Brown Research Center on Aging 101 Sanders Brown Bldg. Lexington, Ky 40536 0230 (606) 323-6040 (606) 323-2866 Fax

Richard Margolin, M.D. Vanderbilt University Division of Geriatric Psychiatry 1500 21st Avenue South Suite 2200 Nashville, Tn 37212 8646 (615) 322-0325 (615) 343-9038 Fax

Questions and Answers: Selegiline and a-tocopherol in the Treatment of Alzheimer's Disease

What did this study examine?

The National Institute on Aging's (NIA's) Alzheimer's Disease Cooperative Study tested the effectiveness of a-tocopherol (also known as vitamin E) and selegiline (also known as Eldepryl) in slowing the progression of Alzheimer's disease. Researchers were interested in these drugs because both are anti-oxidants -substances that counteract oxidative damage. The progressive loss of brain cells that occurs in Alzheimer's disease may be related to oxidative damage. Besides acting as an anti-oxidant, selegiline also increases the supply of dopamine and catecholamines, important brain chemicals whose levels are reduced in Alzheimer's disease.

What were the results?

Taking selegiline, vitamin E, or a combination of the two drugs delayed by about 7 months the time it took for patients to reach one of four milestones: death, institutionalization (moving to a nursing home), loss of the ability to perform activities of daily living, or progression to severe dementia. In one commonly used measure of everyday activities, patients in the three treatment groups showed 25 percent less deterioration in activities such as eating and dressing.

What recommendations come from this study?

The researchers believe it is now reasonable for doctors to consider the use of either selegiline or vitamin E in patients with moderately severe Alzheimer's disease. Today, no other treatments have shown a similar ability to delay important milestones in Alzheimer's disease.

What are the possible side effects or problems of these treatments?

In this study, the selegiline and vitamin E were tolerated well with few side effects. However, with both treatments, there are potential problems as reported in other research. Selegiline, which has been studied very carefully over a long period of time, should not be taken with certain other drugs, specifically anti-depressants or narcotics. Reported side effects of selegiline include fainting, nausea, dizziness, confusion, vivid dreams, and sometimes, low blood pressure. Vitamin E is less well-studied, especially at high doses. As a result, neither the long-term effects nor the potential hazards of such high doses are known. Vitamin E may be associated with increased bleeding in certain people, and some studies have suggested that it should not be used with anti-coagulant medications.

Why were there no advantages to combination therapy?

The researchers tested a combination of selegiline and vitamin E because these drugs seemed to work in different ways in animal and cellular models of AD. These laboratory data strongly suggested that they would have an additive effect. However, in this study, people taking the two drugs did no better than those taking either selegiline or vitamin E alone. These findings may indicate that selegiline and vitamin E both affect Alzheimer's disease in similar ways and, thus, there is no advantage to taking both of them. The results show how important it is to do well-controlled studies in people to determine the effects of drugs and, in particular, combinations of drugs. While laboratory studies may give us an idea of what will work, only controlled studies in humans can tell us if these ideas are correct.

Should people in earlier or later stages of the disease also consider therapy with vitamin E or selegiline? What about taking them for prevention?

This study only addressed patients with moderately severe disease. We do not know whether people in other stages of Alzheimer's disease would benefit from these drugs. The only drugs approved by the Food and Drug Administration (FDA) as safe and effective in treating some symptoms of Alzheimer's disease are tacrine (brand name Cognex) and donepezil (brand name Aricept). There is no evidence that any drug, including vitamin E and selegiline, prevents Alzheimer's disease.

Will vitamin E from a drug store work and what dose should be used?

Vitamin E, though relatively safe, may pose problems for some people. It may be associated with increased risk of bleeding in some people, especially those with bleeding problems. In addition, the study used much higher doses of vitamin E than are typically found in vitamin supplements. High doses of vitamin E and its interaction with other drugs have not been well studied. It is very important to check with a doctor before starting any drug or supplement treatment.

How can someone with Alzheimer's disease get selegiline?

Selegiline is a prescription drug approved by the FDA to treat Parkinson's disease. It is not approved for Alzheimer's disease in the U.S. The decision to take any drug must include weighing benefits and risks. If a doctor concludes that a patient's condition is similar to that of the patients in this study and that the risks of selegiline are not serious for that patient, the doctor may choose to prescribe it. Selegiline must be taken under a doctor's supervision, in part because of its potential side effects as discussed above.

Are vitamin E and selegiline better than drugs currently on the market for Alzheimer's diseasetacrine and donepezil? Should patients take anti-oxidants instead of, or in combination with, these drugs, especially if the current treatment is not working?

This study was not designed to show whether vitamin E and selegiline are better than tacrine and donepezil, which both work by increasing the supply of a brain chemical called acetyl-choline. The research shows that the two kinds of drugs affect different symptoms. In this study, vitamin E and selegiline reduced problems with everyday activities such as bathing and dressing, delayed institutionalization, and slowed the advance to severe dementia over a 2-year period. However, they did not improve memory or cognition, which is seen with tacrine and donepezil. In addition, patients in this study had a more advanced stage of Alzheimer's disease than most patients who have benefited from tacrine and donepezil. There is no evidence that anti-oxidants, such as vitamin E and selegiline, have additive effects when combined with drugs that work on acetylcholine. While it may seem that the combination should not be harmful, no one knows. Only carefully controlled studies in patients can answer that question.

How long will selegiline and vitamin E work? Are there any adverse effects when you stop taking them?

The study showed that 2 years of treatment had a measurable effect. We do not know if the effect would be the same if people stopped treatment or if they continued treatment for a longer or shorter period of time. Researchers did not study what would happen if someone stopped treatment. However, there have been no reports of serious adverse effects from stopping the treatment.

How long should it take before we see results? What results should we see?

Any improvements may not be apparent. These drugs have only been shown to delay the effects of disease. The patient will not be getting better, but he or she will be able to maintain basic functional activities longer.

Will these drugs help patients with other dementias?

We do not know. Other studies have examined these drugs in patients with Huntington's disease and Parkinson's disease, but have found no improvements in cognition or effect on dementia in these diseases.

What further research is needed?

Research is needed to test the effectiveness of anti-oxidants in both the earlier and later stages of Alzheimer's disease. More work needs to be done to determine if these drugs can provide an added benefit when used in combination with other medications to treat dementia.

For further information about Alzheimer's disease, please contact: Alzheimer's Disease Education and Referral (ADEAR) Center tollfree: 1-800-438-4380 website: http://www.alzheimers.org/adear email: adear@alzheimers.org