Alzheimer's Disease Center
University of California, Davis

The Family Connection
Fall/Winter 1997

Research on the treatment of Alzheimer's disease (AD) has advanced at an explosive rate in the last few years. Many of these advances involve new ways of treating patients with AD. Leads on promising treatments have been gleaned from epidemiologic studies as well as the development of new drugs and new treatment trials. Unfortunately, these fascinating and important findings have often prematurely raised hopes of patients and family members, and have also engendered many questions about the scientific literature which is often confusing. In this article, we will provide an idea of the new thinking about treatment of AD which is currently being investigated as well as explain some of these new drugs.

Observational studies

Many new ideas for drug treatment, especially in AD, come from observational studies. Such a study is research in which people in the community are questioned about a variety of habits including diet, occupation, medical illnesses and medications. Those who participate are also studied with different techniques including neuropsychological testing to determine if they suffer from intellectual problems and medical examinations. In projects for the treatment of AD, a number of studies have compared patients who have AD to those without AD, and looked at differences. Some of these studies have found that people without AD were more likely to be taking certain medications, thus suggesting that these medications may have protected these individuals from getting AD.

This sort of epidemiologic data is extremely important. It provides suggestions for drugs or other interventions which may protect against AD, but it does not prove that these drugs undoubtedly were the factor responsible. For example, all people who took a certain drug may have something else in common which the study did not measure and it may have been this factor and not the drug which was protective against AD. Also, observational studies do not usually ascertain what dose and what frequency of administration is necessary to provide benefit. Observational studies may suggest that something is protective against AD, but that is not the same as suggesting that a drug is effective in treating AD once the disease is established. For all of these reasons, even if an observational study suggests that a drug may be useful in AD, a treatment trial or clinical trial must be performed.

Clinicial Trials

Clinical trials are used to test the efficacy of medications using leads from observational studies, as well as medications being developed by the pharmaceutical industry. Initial stages of these trials use very small groups in order to demonstrate that the drugs are safe. This is important only for new medications, not those already established on the market. Once the safety of a drug is established, larger scale clinical trials can begin.

In these trials, patients are randomly assigned to take a drug or a placebo. The placebo, a pill which looks exactly like the drug but has no effect, is very important since both families and physicians may note improvement in patients who are simply given a pill to take even when there may be no chemical effect of the drug. Most such trials are "double blind", so named because neither the patient and family nor the physician knows whether the patient is receiving the drug or placebo. Once patients are placed on the drug and followed for a period of time (generally 6 months to a year in trials of drugs for AD) the results in the patients treated with drugs can be compared to the results in the patients treated with placebo. This comparison generally forms the basis of determining whether the drug is effective. There are many subtle and complicated issues involved in planning a clinical trial. These include how long to follow the patient (this is a big problem in AD, since patients generally change slowly and we must allow a long enough observation period to detect a change), what tests to administer to detect a change, and what doses of drug to prescribe (often a clinical trial will use more than one dose in different groups of subjects). A good clinical trial, with a large number of subjects, careful controls and double blinding is difficult to do and often requires several years to perform, yet there is no substitute for this method in determining whether a drug works.

The Promise of New Drugs?

Tacrine was the first drug approved specifically for the treatment of memory and cognitive loss in patients with AD. This drug works by increasing levels of a particular chemical called acetylcholine in the brain, which is found in lower levels in patients with AD. Acetylcholine is particularly important in memory function. Tacrine was found to produce relatively small but often significant increases in memory ability and other abilities measured through neuropsychological tests in patients with AD. A second recently approved drug donepezil (Aricept), works along the same principles as Tacrine and other drugs which act to increase brain levels of acetylcholine, are being developed and tested by pharmaceutical companies.

While all of these drugs offer some promise of improving symptoms of AD, none of these drugs are targeted to stop the progression of the disease or to treat the basic mechanism in the disease. This is not surprising, since the cause of the disease is unknown. In addition, some of the drugs are limited by side effects. Patients often show no benefit from treatment, and the benefits shown by most patients are relatively small and temporary. For these reasons, the search for other types of drugs is also a major focus of energy.

New Drugs on Trial

A number of drugs are currently in clinical trials based upon epidemiologic findings. Two of these drugs have made headlines because they are so commonly prescribed -- estrogen and non-steroidal anti-inflammatory drugs such as Motrin or Advil. In several epidemiological trials, people taking these drugs were found to have lower risk of developing AD. As noted, clinical trials must be performed in order to determine whether the drug itself is truly beneficial and whether or not benefit can be obtained by people with AD. Although a few very small scale trials suggest that both drugs may be helpful, large scale trials are currently underway. These results should become available in the next several years. Another treatment currently being tested is vitamin E . This too is in the final stages of a clinical trial, and results should be available in the near future.

New Discoveries

Finally, new classes of drugs which offer hope for AD patients are frequently discovered. Most recently, a member of a class of drugs called AMPAKINES was found to improve memory performance in older people who did not have AD. This drug has not yet been tested in patients with AD, and will require a large scale clinical trial before its efficacy can be established.

It is important to keep in mind that the media often releases news on drugs at very early stages of their development. While reports of new drugs and discoveries in epidemiologic surveys are important, all of these reports must be followed up with large scale clinical trials before new drugs can be established as safe and effective.