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The search for therapies

This is an exciting time in Alzheimer's research. You may have heard or read about a variety of therapies on the horizon, some in the form of new drugs that may be able to cure the disease by blocking the chain of events that underlie its destructive process. Still, while scientists believe they are finally beginning to close in on this elusive disease, a cure is years away.

There is currently no treatment that prevents or stops cognitive deterioration. Available medications can only alleviate symptoms temporarily. The hope and expectation is that ongoing research efforts will yield therapies that bring about better, longer-lasting improvements in memory and other cognitive functions.

A number of medication options do exist for behavior problems, such as outbursts of anger, which sometimes develop in someone with Alzheimer's. These are best used in conjunction with environmental changes, such as simplifying the home environment (see "Techniques for living with someone with Alzheimer's disease").

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Drugs for memory and cognitive function

The FDA has approved five drugs for the treatment of Alzheimer's disease: donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne, formerly Reminyl), tacrine (Cognex), and memantine (Namenda). All these prescription medications work by affecting particular chemicals in the brain and offer modest improvements in memory and cognitive function in some people with Alzheimer's (see Table 3).

Donepezil, rivastigmine, galantamine, and tacrine belong to a class of drugs called acetylcholine esterase inhibitors. They work to raise the levels of acetylcholine in the brain, because a deficiency in this neurotransmitter is believed to account for the memory problems of Alzheimer's disease. They seem to work by blocking an enzyme that destroys acetylcholine, which presumably makes more acetylcholine available for transmitting impulses from one brain cell to another. The drugs are effective for people with mild to moderate Alzheimer's disease. Tacrine is rarely used because it's been associated with severe liver problems.

Only about 30%–50% of the people who take this class of drugs show benefits. These medications may temporarily stabilize or improve memory problems and other cognitive symptoms. For example, one 2001 study found that taking donepezil for at least 9 months postponed a patient's need to move to a nursing home by about 21 months.

Memantine has a different mode of action. It is an NMDA (N-methyl-D-aspartate) antagonist — it works by blocking glutamate, another neurotransmitter, from attaching to NMDA receptors in the brain. This is beneficial because glutamate is an excitotoxin, a neurotransmitter that usually activates neurons but in excessive amounts can destroy them. Research suggests that excitotoxins may cause some of the neuron degeneration that occurs with Alzheimer's disease (see "Antioxidants").

Memantine is used to treat symptoms of moderate to severe Alzheimer's disease. Several studies show that people in this stage of Alzheimer's who took memantine had better scores on tests of cognitive functions and daily functioning than did similar people who took a placebo. Studies are under way to see if memantine can also help people with mild to moderate symptoms.

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Medications for behavior problems

Brain damage influences the way people act and react. As comprehension falters, emotional and behavior problems can soar. When the environment seems too confusing and overwhelming, someone with Alzheimer's may become angry or even violent. Although no treatment can halt the cognitive deterioration of Alzheimer's, there are ways to diminish or even resolve some behavior problems. For example, simplifying the environment, establishing a routine that places minimal demands on the individual, and using simple management techniques have all proved effective (see "Techniques for living with someone with Alzheimer's disease").

Sometimes behavior disturbances are rooted in a medical problem. Agitation, for example, may signal physical discomfort. When an undesirable behavior appears suddenly or the person fails to respond to management techniques, he or she should be evaluated by a physician. Treatment of an underlying condition sometimes resolves what appeared to be solely a behavior problem. For example, relieving neck pain caused by arthritis might stop a person from wandering at night.

Behavior management alone is not always sufficient. In some cases, a physician may prescribe psychiatric medications. Try not to expect immediate results, because physicians usually begin with a low dose and increase it gradually. Care is required because psychiatric medications can produce serious side effects, particularly in older people.

In addition, some medications, such as antidepressants, must be given for several weeks before their benefits become apparent. Keep in mind that individual responses to these medications vary considerably. The same drug that helps one person may not be effective or may even worsen symptoms in another individual.

Three classes of drugs may be used to treat emotional and behavior problems: antidepressants, anti-anxiety drugs (also called minor tranquilizers), and antipsychotics (also called major tranquilizers or neuroleptics).

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Antidepressants

In addition to relieving depression, antidepressants often enhance the social functioning of a person with Alzheimer's disease, as well as improve appetite and sleep and increase energy (see Table 4). But side effects can be a problem.

One of the most serious side effects is orthostatic hypotension, a sudden drop in blood pressure when the individual stands up, which is a common cause of fainting. This sudden drop in blood pressure not only increases the risk of falling and being injured but may also cause the heart rate to speed up, which can exacerbate heart problems. But this side effect is more common with tricyclic antidepressants than with the selective serotonin reuptake inhibitors (SSRIs).

Tricyclic antidepressants also have a sedating effect, which may be desirable at night, but not during the day. In addition, these drugs are anticholinergic — that is, they block acetylcholine, which is already at reduced levels in individuals with Alzheimer's — and can thus worsen cognitive function and cause delirium. Other side effects include dry mouth, constipation, difficulty urinating, blurred vision, and increased heart rate.

The SSRIs — including fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) — act on serotonin instead of acetylcholine. Unlike tricyclics, they rarely cause dry mouth, constipation, or dizziness. Nor do they disrupt the heart rhythm. However, in some people, they cause insomnia, nervousness, agitation, and irritability. Other side effects can include diarrhea, nausea, loss of appetite, weight loss, sweating, sexual problems, and headache. These side effects can often be eliminated if the dose is reduced.

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Anti-anxiety drugs

Doctors are likely to prescribe anti-anxiety drugs for people with Alzheimer's disease who are anxious, restless, or agitated. Because they are also sedating, these medications often relieve sundowning and insomnia (see Table 5). Unlike antidepressants, anti-anxiety drugs exert their effects quickly, often within an hour. However, older people are especially sensitive to these drugs, and over time, toxic levels can accumulate in the body and cause serious reactions, including oversedation and loss of coordination.

To prevent these side effects, physicians favor anti-anxiety medications that have a relatively short duration and can be given in small doses at intervals during the day. People who experience only occasional anxious episodes can be given a fast-acting anti-anxiety drug as needed, rather than taking scheduled doses.

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Antipsychotics

Antipsychotic drugs may be useful in managing behavior problems that result from delusions, hallucinations, paranoia, severe agitation, and hostility (see Table 6). Although a 2006 study in the New England Journal of Medicine found that these drugs were no more effective than placebo in calming people with Alzheimer's, and therefore questioned the wisdom of prescribing them, doctors continue to recommend antipsychotics in some cases, as they may help some people temporarily.

Within the first two months of therapy, a person may develop symptoms that mimic Parkinson's disease, including slowed movements, tremors, rigid muscles, a shuffling walk, drooling, and a masklike expression. These symptoms can be managed with an anti-Parkinson drug. High doses of antipsychotic drugs over a long period of time can cause tardive dyskinesia, involuntary writhing movements of the arms, legs, and tongue. Fortunately, this is uncommon at the doses used to treat dementia. And compared with older antipsychotic drugs, the newer ones are less likely to cause either Parkinsonian symptoms or tardive dyskinesia.

Some people have a paradoxical reaction to antipsychotics, that is, they become even more agitated and restless. A lower dosage, different medication, or the addition of an anti-Parkinson drug usually resolves this problem.

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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.

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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.

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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.

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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.

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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.

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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.

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Review Date: 2007-01-01

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