• Highlights
• Introduction
• Causes
• Risk Factors
• Prevention
• Symptoms
• Diagnosis
• Medications
• Stages
• Resources
• References

Alzheimer's disease

Description

An in-depth report on the causes, diagnosis, and treatment of Alzheimer's disease.

Medications

Most drugs currently being used or that are under investigation to treat Alzheimer's are aimed at slowing progression. To date, none are cures. In fact, the improvements from some of these drugs may be so modest that even the patients and their families are not aware of them. Even in these cases, however, the drugs may delay the need for admission to nursing homes.

There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease:

• Cholinesterase inhibitors (generally used to treat mild-to-moderate Alzheimer's)
• N-methyl-D-aspartate (NMDA) receptor antagonists (used to treat moderate-to-severe Alzheimer's)

Cholinesterase Inhibitors

Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001).

Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about concurrent use of NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.

• Donepezil. Donepezil (Aricept) is taken once a day and has only modest benefits but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without the ApoE4 gene. In a 2004 study, donepezil appeared to help improve memory and daily living ability in patients with moderate-to-severe Alzheimer's when taken in combination with memantine. Several trials, including an important 2005 New England Journal of Medicine ( NEJM ) study, have found that donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. In the NEJM study, donepezil slowed progression during the first year of therapy, but demonstrated no benefits by the conclusion of the 3-year trial.
• Rivastigmine. Rivastigmine (Exelon) targets two enzymes (the major one, acetylcholinesterase, and butyrylcholinesterase). It is taken twice a day. This drug may be particularly beneficial for patients with rapidly progressing disease. It has slowed or slightly improved disease status even in patients with advanced disease. Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.
• Galantamine (Razadyne). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time. In 2005, the name of galantamine was changed from Reminyl to Razadyne.
• Tacrine. Tacrine (Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.

About half of patients with mild to moderate disease show slight improvement with these drugs. Comparative studies have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs used often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro -cholinergic drugs. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs the deterioration continues. In 2005, the United Kingdom’s National Institute for Clinical Excellence (NICE) recommended against the use of donepezil, rivastigmine, galantamine, and memantine for Alzheimer’s disease treatment. The agency contended that the costs of these drugs outweigh their modest benefits.

N-methyl-D-aspartate (NDMA) Receptor Antagonist

Memantine (Namenda) is currently the only drug approved for treatment of moderate-to-severe Alzheimer’s disease. (Cholinesterase inhibitors are generally used to treat mild-to-moderate stages of the disease.) By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.

Memantine is prescribed either alone or in combination with donepezil. Studies indicate that memantine may help improve cognitive function and delay the progression of Alzheimer’s disease for up to one year. Side effects are generally mild but may include dizziness, drowsiness, or fainting.

In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In a 2004 study, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least 6 months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters.

Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Treatment

There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been suggested that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.

Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. Since the completion of these studies, rofecoxib was withdrawn from the market and the NIH suspended a clinical study assessing naproxen’s preventive benefits (see Nonsteroidal Anti-Inflammatory Drugs as Prevention). As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.

Nicotine Replacement

Nicotine enhances the actions of the cholinergic system (which is depleted in Alzheimer's disease) and is known to improve concentration and memory in the short term. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.

Alternative Treatments

Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. A 2002 study of healthy people who took over-the-counter ginkgo for six weeks reported no improvements in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. The herb poses a small increased risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E.

Turmeric. Studies suggest that circumin, a compound found in the spice turmeric, has properties that may protect against Alzheimer's disease process.

Melatonin. Melatonin, a natural hormone involved in sleep regulation, is of interest to researchers. It is an antioxidant, it may break down beta amyloid, and it is able to pass through blood-brain barrier. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some studies reported slower progression of mental impairment.

Investigative Drugs

A number of drugs are being investigated for treatment and prevention of Alzheimer's disease. Intense areas of research are focusing on drugs that prevent beta amyloid build-up, its toxic effects on nerve cells, or other mechanisms of the disease process.

• Alzhemed . Alzhemed (NC-758) is an experimental drug designed to prevent beta-amyloid accumulation in the brain.
• Flurizan (MPC-7869). Flurizan may help reduce amyloid plaque development. It is currently being studied in Phase III trials for adults with mild Alzheimer’s disease
• Antioxidants . Vitamin E and selenium are being investigated for their preventive effects. Antioxidant treatment trials include curcumin, (the yellow pigment found in turmeric spice), and a combination trial with fish oil and alpha-lipoic acid. A 2005 study found no benefit for Vitamin E treatment.
• Huperzine alpha . This Chinese herbal cholinesterase inhibitor is being studied for improvement of cognitive function.
• Antipsychotics/Anticonvulsants . The antipsychotic drug quetiapine (Seroquel) is being investigated for treatment of AD-associated agitation and psychosis. Valproate (Depakote), an anticonvulsant drug, is in trials for delaying emergence or slowing the progression of agitation and psychosis.
• Statins . Simvastatin, and other cholesterol-lowering drugs, are being investigated for slowing the progression of Alzheimer’s disease.

Treating Symptoms Associated with Alzheimer's

Depression. Major depression with dementia that occurs in elderly people may be an early sign of Alzheimer's. In such cases, it precedes Alzheimer's by 2 years or less. (It is, in fact, sometimes difficult to differentiate major depression from early stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients.

Apathy. Depression is often confused with apathy. According to one study, apathy is more common than depression in patients with Alzheimer's disease. It responds to stimulants such as methylphenidate (Ritalin) rather than antidepressants. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless.

Psychosis. Antipsychotic drugs can treat verbally or physically aggressive behavior and hallucinations. Because older antipsychotic drugs such as haloperidol (Haldol) have severe side effects, most doctors now prescribe newer atypical antipsychotics such as risperidone (Risperdal) or olanzapine (Zyprexa). Although these new antipsychotic drugs appear to have fewer side effects than older drugs, a 2005 study suggested that they may pose a slightly increased risk for death in patients with Alzheimer’s disease or dementia. A 2006 study published in the New England Journal of Medicine found that there are no differences in treatment between placebo and Zyprexa, Risperdal, and the investigational drug Seroqul when used to calm agitation and aggression in people with Alzheimer's. More research is needed.

Some experts recommend that doctors delay prescribing antipsychotic medication unless absolutely necessary. They recommend first trying behavioral treatments and antidepressant drugs. Anti-seizure drugs such as carbamazepine (Tegretol) or valproate (Depakote) can also sometimes treat agitation and other psychotic symptoms.

Disturbed Sleep. Patients with Alzheimer's disease commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping drugs such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata) or sedating antidepressants such as trazodone (Desyrel, Molipaxin) may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.

• Review Date: 5/22/2006
• Reviewed By: Harvey Simon, M.D., Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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