All of the prescription medications currently approved by the U.S. Food and Drug Administration (FDA) to treat cognitive Alzheimer symptoms are in a class of drugs called cholinesterase inhibitors. Three cholinesterase inhibitors are commonly prescribed—donepezil (Aricept^®), approved in 1996, rivastigmine (Exelon^®), approved in 2000, and galantamine (Reminyl^®), approved in 2001. Tacrine (Cognex^®), the first drug in this class, was approved in 1993 but is rarely prescribed today because of associated side effects, including possible liver damage.

Vitamin E supplements are frequently prescribed and have become a part of a standard treatment regimen for most people with Alzheimer's.

There is a new drug called Memantine that was approved in May 2002 by the European Union's Committee for Proprietary Medicinal Products for the treatment of moderately severe to severe Alzheimer's throughout the European Union, where it is marketed by Lundbeck as Ebixa^®. It is now under development by Forest Laboratories, Inc. for marketing in the United States, and it should either be approved or not approved by the FDA by the end of 2003. The U.S. single-therapy trial tested Memantine's effects in people with moderately severe to severe Alzheimer's, the stages when individuals develop problems with dressing, bathing and other daily activities and when behavioral symptoms that often complicate Alzheimer's tend to become significant. As a result, these are also the stages that cause the greatest caregiver burden and represent the points at which families tend to move relatives with Alzheimer's from their homes into assisted living facilities or nursing homes. In the trial, participants who received 10 milligrams of Memantine twice a day during the six months of the study showed significantly slower decline in thinking skills and ability to perform daily self-care activities than enrollees who received a placebo.

For more information on Memantine, click here.

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Cholinesterase inhibitors are designed to enhance memory and other cognitive functions by influencing certain chemical activities in the brain. Acetylcholine is a chemical messenger in the brain that scientists believe is important for the function of brain cells involved in memory, thought, and judgment. Acetylcholine is released by one brain cell to transmit a message to another. Once a message is received, various enzymes, including one called acetylcholinesterase, break down the chemical messenger for reuse.

In the Alzheimer-afflicted brain, the cells that use acetylcholine are damaged or destroyed, resulting in lower levels of the chemical messenger. A cholinesterase inhibitor is designed to stop the activity of acetylcholinesterase, thereby slowing the breakdown of acetylcholine. By maintaining levels of acetylcholine, the drug may help compensate for the loss of functioning brain cells.

Galantamine also appears to stimulate the release of acetylcholine and to strengthen the way that certain receptors on message-receiving nerve cells respond to it.

Donepezil and rivastigmine were associated with better performance in memory and thinking tests in patients who were on the active medication compared with patients taking a placebo (an inactive substance). It should be stressed that the degree of improvement was modest, and more than half of the patients showed no improvement at all.

Galantamine also resulted in modest improvements in clinical trials. Additional research will help scientists determine how many individuals are likely to benefit from the drug.

Donepezil (Aricept^®) is a tablet and can be administered once daily. Generally, the initial dose is 5 mg a day (usually given at night). After four to six weeks, if it is well tolerated, the dose is often increased to the therapeutic goal of 10 mg a day. Rivastigmine (Exelon^®) is available as a capsule or as a liquid. The dosage is gradually increased to minimize side effects. Usually the medication is started at 1.5 mg daily. After two weeks the dosage is increased to 1.5 mg twice a day. The therapeutic goal is to increase the dosage gradually every two weeks to reach 6 to 12 mg a day. There is a greater frequency of side effects at these higher doses; however, taking drugs with meals may be helpful in reducing the occurrence of side effects.

Galantamine (Reminyl^®) became available in pharmacies in May 2001. It is supplied in the form of tablets in strengths of 4, 8, and 12 milligrams.

Generally, donepezil is well tolerated. Because experience with rivastigmine and galantamine is limited, it is unknown how well these drugs will be tolerated in the general population. Symptoms such as nausea, vomiting, loss of appetite, and increased frequency of bowel movements might be expected with any cholinesterase inhibitor. It is strongly recommended that a physician who is comfortable and experienced in using these medications monitor patients treated with any of these compounds and that the recommended guidelines be strictly observed. There is no evidence or reason to believe that combining the drugs would be any more beneficial than taking either one alone, and it is likely that combining the drugs would result in greater side effects.

© Alzheimer's Disease and Related Disorders Association, Inc

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The normal cell function termed "oxidative metabolism" results in byproducts known as free radicals. Free radicals are highly reactive compounds that quickly "attack" other cell substances, causing damage to the cell wall, metabolic machinery, and genetic material (DNA). The cells have natural defenses against this damage, which include the antioxidants vitamins C and E, but with age some of these protective mechanisms decline. Brain cell damage caused by free radicals may play a role in Alzheimer's disease.

Research reported in the April 24, 1997, issue of the New England Journal of Medicine investigated the effectiveness of vitamin E and selegiline, a drug with antioxidant properties that is prescribed for treating Parkinson's disease. The research was part of the Alzheimer's Disease Cooperative Study, a consortium of academic Alzheimer research centers sponsored by the U.S. National Institute on Aging. The study suggests that either selegiline or vitamin E delays the occurrence in patients with Alzheimer's disease to one or more of the following "endpoints": death, institutionalization, progression from moderate to severe dementia, or loss of ability to perform two of three basic activities of daily living (eating, grooming, or toileting). When both agents were given together, there was also a delay in progression of Alzheimer's disease as measured by these endpoints. However, both agents together did not help more than either drug alone. These agents did not improve memory and thinking test scores.

These results are encouraging but as yet have not been confirmed by other studies. We also do not know if these agents would be helpful in milder or severe stages of Alzheimer's disease. There was no evidence that intellectual deterioration was slowed. Finally, any medication may have side effects or potential interactions with other drugs. For example, it is known that certain doses of selegiline (higher than those used in the study) can lead to serious interactions with some types of foods and certain medications.

Vitamin E worked at least as well as selegiline on Alzheimer's progression in this study and had fewer side effects. Vitamin E also costs less. For these reasons it is preferred over selegiline in Alzheimer's disease treatment. Vitamin E is considered to be a "benign" medication and most people can take it without side effects. However, any change in medications should first be discussed with your primary care physician because all medication can cause side effects or interactions with other medications. People taking "blood-thinners" like warfarin (Coumadin^®), ticlopidine (Ticlid^®), and others may not be able to take Vitamin E or will need to be monitored closely by their physician if they are taking Vitamin E.

Exactly what dose of vitamin E is the "best" is not known. The doses of vitamin E in the study were 1,200 IU twice daily. Other doses need to be studied to answer this question confidently. Many doctors recommend 400 IU twice daily because they believe this dosage to be safe for most individuals and it should have the antioxidant effect desired in the brain.

Prepared by John C. Morris, MD, professor of neurology at Washington University at St. Louis

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