Therapies Under Investigation - The Search For Therapies: Alzheimers

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Therapies under investigation

The goal of future Alzheimer's therapies is to prevent the loss of synapses and neurons in the areas of the brain involved in memory and cognition. Only then can scientists slow the course or arrest the progress of the disease. Because a complex and long-term series of events is believed to cause Alzheimer's disease, researchers are investigating several compounds that intervene in this destructive process by different means.

Anti-amyloid drugs and antioxidant drugs offer two particularly promising strategies. Each would target a process thought to be central to the loss of synapses and nerve cells. Anti-amyloid drugs would block the production of beta-amyloid, which many scientists believe sets off the destructive cascade of events that leads to neuron death. The antioxidant drugs could reduce the neuron damage caused by free radicals. Another promising area of research involves the use of stem cells to replace dying cells with healthy ones.

Amyloid production blockers

Some researchers are optimistic about the prospect of blocking the production of amyloid plaques, which are believed to be toxic to neurons. Specifically, these researchers are developing compounds that act on enzymes that play an essential role in producing amyloid.

This process starts with a protein produced by healthy neurons called amyloid precursor protein (APP), which crosses the membrane of a cell. Normally, the protein is cut in half by an enzyme called alpha-secretase, and the resulting protein fragments are believed to be nontoxic. But APP can also be cut by two other enzymes, beta- and gamma-secretase. When this happens, the result is the shorter, stickier beta-amyloid protein. Beta-amyloid molecules can either join together and remain soluble or fold into fibrils (the amyloid plaques); both the soluble and aggregated fibril forms of beta-amyloid are believed to be toxic to neurons.

Scientists have identified the structure of all three enzymes involved in processing APP. This knowledge has paved the way for attempts to produce anti-amyloid drugs that either stimulate alpha-secretase or block beta- and gamma-secretase. Several pharmaceutical companies are developing compounds that inhibit either beta- or gamma-secretase.

Antioxidants

Researchers are also studying the biochemistry of brain tissue damage, particularly the activities of two types of substances normally produced in the body. Excitotoxins, mentioned earlier, are neurotransmitters that normally stimulate communication between neurons but in excessive amounts can degrade them. Free radicals are negatively charged, extremely reactive molecules that have been implicated in many types of tissue damage, including neuron death. Free radicals can push excitotoxins over the edge, so to speak, to make them destructive.

Research indicates that excitotoxins and free radicals may account for some of the neuron degeneration that occurs with Alzheimer's disease and Parkinson's disease. Selegiline (Eldepryl), a drug that initially appeared to slow the progression of Parkinson's disease, is an antioxidant that inhibits the formation of free radicals in brain tissue. A team led by researchers from Columbia University tested selegiline and vitamin E (also an antioxidant) in people with moderately severe Alzheimer's disease.

The study found that selegiline and high doses of vitamin E (2,000 IU) individually might modestly slow the progression of Alzheimer's. Combining the two offered no additional benefits. This information was particularly exciting for scientists because it offered important clues for finding other, more powerful, antioxidant drugs that could someday treat or even prevent the disease.

Research on whether vitamin E, alone or with other antioxidants, can help prevent Alzheimer's disease has been mixed. Two studies published in 2002 looked at the impact of vitamin E from food sources, instead of supplements. Both found that diets rich in vitamin E may help lower the risk of developing Alzheimer's disease. Interestingly, while one of these studies found that risk declined only among people who did not have the E4 allele, the other found that even those with the E4 allele could benefit. The National Institute on Aging is conducting a large clinical trial to see if a combination of vitamin E and selenium, an antioxidant mineral, can safely and effectively prevent Alzheimer's disease.

Today, researchers recommend that people take no more than 400 IU of vitamin E a day. Higher amounts increase the risk of death from various causes, according to a 2004 meta-analysis of published research. If you have a bleeding disorder or are taking anticoagulant medications such as aspirin, talk with your doctor before taking vitamin E supplements in any amount. Vitamin E can be dangerous because it promotes bleeding.

Ginkgo biloba. This herb is an antioxidant that is popular for its potential to treat and prevent Alzheimer's disease. However, research on its effectiveness is inconclusive. A 2002 Cochrane Collaboration review of the clinical trials studying ginkgo biloba's effects on people with dementia and other cognitive difficulties found promising results. People who took doses of less than 200 milligrams a day showed improvements in cognition, activities of daily living, and mood compared with people who took a placebo. However, many of the earliest studies were poorly done, the researchers concluded, and the better, more studies had inconsistent findings. A larger trial is needed to establish ginkgo biloba's effectiveness in treating Alzheimer's disease and other forms of dementia.

If you are considering taking ginkgo biloba, keep in mind that although it is safe in most circumstances, it can be dangerous to some people. You should avoid taking the herb if you regularly use medications that thin the blood — such as aspirin and other nonsteroidal anti-inflammatory agents, heparin, or warfarin (Coumadin) — or if you have a seizure disorder.

Alzheimer's disease vaccine

One day it may be possible to prevent or treat Alzheimer's disease with a vaccine. In fact, several vaccines are under development.

The very notion of an Alzheimer's vaccine is a bit unconventional. Most vaccines stimulate the immune system to produce antibodies against a virus. But several years ago, researchers found that injecting beta-amyloid protein into mice stimulated the immune system to produce antibodies against beta-amyloid. These antibodies accomplished a remarkable feat: They cleared beta-amyloid plaques, the physical signs of Alzheimer's disease, from the brain.

Then, in 2001, a vaccine called AN-1792 was tested on 300 people with Alzheimer's disease to see if it was safe and effective in improving symptoms. Another 75 people took a placebo. The trial was discontinued in 2002 when 15 people given the vaccine developed a nonfatal brain inflammation. With treatment, all improved or recovered. Researchers continue to follow other study participants, and they have found that 20% of those who were vaccinated had an immune response, and that all of those who did also show marked improvements in activities of daily living, a sign that the vaccine slowed the progression of the disease. The greatest improvements are in the people with the greatest antibody response to the vaccine.

In addition, autopsies of the vaccinated participants who later died of Alzheimer's-related complications showed that large areas of their brains were clear of amyloid plaques, an indication that the vaccine may have reversed the brain damage caused by Alzheimer's disease.

Researchers are trying to develop a safer Alzheimer's disease vaccine. One approach is "passive vaccination," the use of antibodies to beta-amyloid to clear the brain of amyloid plaque. In experiments with mice, passive vaccination has had the same plaque-clearing effects as "active" vaccination with beta-amyloid itself.

Another experimental vaccine is a modified form of amyloid protein given in the form of nose drops. In a study published in the Journal of Neuroscience in 2006, the nasal vaccine improved learning and memory in mice and reduced amyloid deposits in their brains.

Estrogen therapy

Even though large studies show that postmenopausal hormone therapy increases the risk of dementia in healthy women, some researchers see potential in other types of estrogen therapy, either as treatments for women with Alzheimer's disease or as preventive measures. The reason for hope is evidence that estrogen, in some circumstances, improves cognitive function.

Some clinical trials are looking at raloxifene (Evista), a medication for osteoporosis and breast cancer. Raloxifene belongs to a class of drugs called selective estrogen receptor modulators, which act like estrogen in some tissues and block estrogen in others, and therefore do not cause breast and uterine cancers. A trial of 5,386 postmenopausal women around the world found that those who took raloxifene had two-thirds less a risk of developing mild cognitive impairment than women who took a placebo. Ongoing research at the University of Wisconsin is focusing on whether raloxifene improves cognitive function and the ability to carry out activities of daily living in women with Alzheimer's disease.

A clinical trial sponsored by the National Institute on Aging is testing whether an estrogen patch can improve memory and the ability to live independently among postmenopausal women with mild to moderate Alzheimer's disease. The study involves about 160 women ages 55–90.

Implanting healthy neurons

As mentioned earlier, experts believe that memory problems may stem from low levels of acetylcholine. In theory, transplanting healthy cholinergic neurons (which produce acetylcholine) into the brain would be a direct way to restore acetylcholine levels. The idea arose from Parkinson's disease–related experiments in which dopamine-producing cells were transplanted into the brain.

Whether a similar technique might work in Alzheimer's remains uncertain. It may be possible for stem cells to become cholinergic neurons, which, in turn, would restore healthy levels of acetylcholine. However, this approach would not affect the other neurotransmitter deficits, synaptic loss, and neuronal degeneration that cause dementia.

Last updated:	January 23, 2007