Alzheimer's Disease 

Introduction

Alzheimer’s (AHLZ-high-merz) disease is a progressive brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. As Alzheimer’s progresses, individuals may also experience changes in personality and behavior, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations.

There are now more than 5 million people in the United States living with Alzheimer’s disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early-onset Alzheimer’s disease and other dementias.

Although there is currently no cure for Alzheimer’s, new treatments are on the horizon as a result of accelerating insight into the biology of the disease. Research has also shown that effective care and support can improve quality of life for individuals and their caregivers over the course of the disease from diagnosis to the end of life.

Currently, there is no cure for Alzheimer's. But drug and non-drug treatments may help with both cognitive and behavioral symptoms.

Researchers are looking for new treatments to alter the course of the disease and improve the quality of life for people with dementia.

Coenzyme Q10

Coenzyme Q10, or ubiquinone, is an antioxidant that occurs naturally in the body and is needed for normal cell reactions to occur. This compound has not been studied for its effectiveness in treating Alzheimer’s.

A synthetic version of this compound, called idebenone, was tested for Alzheimer’s disease but did not show favorable results. Little is known about what dosage of coenzyme Q10 is considered safe, and there could be harmful effects if too much is taken.

Ginkgo biloba

Ginkgo biloba is a plant extract containing several compounds that may have positive effects on cells within the brain and the body. Ginkgo biloba is thought to have both antioxidant and anti-inflammatory properties, to protect cell membranes, and to regulate neurotransmitter function. Ginkgo has been used for centuries in traditional Chinese medicine and currently is being used in Europe to alleviate cognitive symptoms associated with a number of neurological conditions.

In a study published in the Journal of the American Medical Association (October 22/29, 1997), Pierre L. Le Bars, MD, PhD, of the New York Institute for Medical Research, and his colleagues observed in some participants a modest improvement in cognition, activities of daily living (such as eating and dressing), and social behavior. The researchers found no measurable difference in overall impairment.

Results from this study show that ginkgo may help some individuals with Alzheimer’s disease, but further research is needed to determine the exact mechanisms by which Ginkgo works in the body. Also, results from this study are considered preliminary because of the low number of participants, about 200 people.

Few side effects are associated with the use of Ginkgo, but it is known to reduce the ability of blood to clot, potentially leading to more serious conditions, such as internal bleeding. This risk may increase if Ginkgo biloba is taken in combination with other blood-thinning drugs, such as aspirin and warfarin.

Currently, multicenter trial with about 3,000 participants is investigating whether Ginkgo may help prevent or delay the onset of Alzheimer’s disease or vascular dementia.

Huperzine A

Huperzine A (pronounced HOOP-ur-zeen) is a moss extract that has been used in traditional Chinese medicine for centuries. Because it has properties similar to those of FDA-approved Alzheimer medications, it is promoted as a  treatment for Alzheimer’s disease.

Evidence from small studies shows that the effectiveness of huperzine A may be comparable to that of the approved drugs. Large-scale trials are needed to better understand the effectiveness of this supplement.

In Spring 2004, the National Institute on Aging (NIA) launched the first U.S. clinical trial of huperzine A as a treatment for mild to moderate Alzheimer’s disease.

Because huperzine A is a dietary supplement, it is unregulated and manufactured with no uniform standards. If used in combination with FDA-approved Alzheimer drugs, an individual could increase the risks of serious side effects.

Omega-3 fatty acids

The U.S. Food and Drug Administration (FDA) permits supplements and foods to display labels with “a qualified health claim” for two omega-3s called docosahexaneoic acid (DHA) and eicosapentaenoic acid (EPA). The labels may state, “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease,” and then list the amount of DHA or EPA in the product. The FDA recommends taking no more than a combined total of 3 grams of DHA or EPA a day, with no more than 2 grams from supplements.

Research has also linked high intake of omega-3s to a possible reduction in risk of dementia or cognitive decline. The chief omega-3 in the brain is DHA, which is found in the fatty membranes that surround nerve cells, especially at the microscopic junctions where cells connect to one another.

A Jan. 25, 2006, literature review by the Cochrane Collaboration found that published research does not currently include any clinical trials large enough to recommend omega-3 supplements to prevent cognitive decline or dementia. But the reviewers found enough laboratory and epidemiological studies to conclude this should be a priority area for further research.

According to the review, results of at least two larger clinical trials are expected in 2008. The Cochrane Collaboration is an independent, nonprofit organization that makes objective assessments of available evidence on a variety of issues in treatment and health care.

Theories about why omega-3s might influence dementia risk include their benefit for the heart and blood vessels; anti-inflammatory effects; and support and protection of nerve cell membranes. There is also preliminary evidence that omega-3s may also be of some benefit in depression and bipolar disorder (manic depression).

A report in the April 2006 Nature described the first direct evidence for how omega-3s might have a helpful effect on nerve cells (neurons). Working with laboratory cell cultures, the researchers found that omega-3s stimulate growth of the branches that connect one cell to another. Rich branching creates a dense “neuron forest,” which provides the basis of the brain’s capacity to process, store and retrieve information.

See also the 2004 FDA press release announcing extension of the qualified health claim for omega-3s and coronary heart disease from supplements to foods.

Phosphatidylserine

Phosphatidylserine (pronounced FOS-fuh-TIE-dil-sair-een) is a kind of lipid, or fat, that is the primary component of cell membranes of neurons. In Alzheimer’s disease and similar disorders, neurons degenerate for reasons that are not yet understood. The strategy behind the possible treatment with phosphatidylserine is to shore up the cell membrane and possibly protect cells from degenerating.

The first clinical trials with phosphatidylserine were conducted with a form derived from the brain cells of cows. Some of these trials had promising results. However, most trials were with small samples of participants.

This line of investigation came to an end in the 1990s over concerns about mad cow disease. There have been some animals studies since then to see whether phosphatidylserine derived from soy may be a potential treatment. A report was published in 2000 about a clinical trial with 18 participants with age-associated memory impairment who were treated with phosphatidylserine. The authors concluded that the results were encouraging but that there would need to be large carefully controlled trials to determine if this could be a viable treatment.

Coral calcium

“Coral” calcium supplements have been heavily marketed as a cure for Alzheimer’s disease, cancer, and other serious illnesses. Coral calcium is a form of calcium carbonate claimed to be derived from the shells of formerly living organisms that once made up coral reefs.

In June 2003, the Federal Trade Commission (FTC) and the Food and Drug Administration (FDA) filed a formal complaint against the promoters and distributors of coral calcium. The agencies state that they are aware of no competent and reliable scientific evidence supporting the exaggerated health claims and that such unsupported claims are unlawful.

Coral calcium differs from ordinary calcium supplements only in that it contains traces of some additional minerals incorporated into the shells by the metabolic processes of the animals that formed them. It offers no extraordinary health benefits. Most experts recommend that individuals who need to take a calcium supplement for bone health take a purified preparation marketed by a reputable manufacturer.

Treatment -

Five prescription drugs currently are approved by the U.S. Food and Drug Administration to treat people who have been diagnosed with Alzheimer's disease (AD). Treating the symptoms of AD can provide patients with comfort, dignity, and independence for a longer period of time and can encourage and assist their caregivers as well.

It is important to understand that none of these medications stops the disease itself.

Treatment for Mild to Moderate AD

Four of these medications are called cholinesterase inhibitors. These drugs are prescribed for the treatment of mild to moderate AD. They may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. The medications are: Razadyne® (formerly known as Reminyl®) (galantamine), Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine). Scientists do not yet fully understand how cholinesterase inhibitors work to treat AD, but current research indicates that they prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking. As AD progresses, the brain produces less and less acetylcholine; therefore, cholinesterase inhibitors may eventually lose their effect.

No published study directly compares these drugs. Because all four work in a similar way, it is not expected that switching from one of these drugs to another will produce significantly different results. However, an AD patient may respond better to one drug than another. Cognex® (tacrine) is no longer actively marketed by the manufacturer.

Treatment for Moderate to Severe AD

The fifth approved medication, known as Namenda® (memantine), is an N-methyl D-aspartate (NMDA) antagonist. It is prescribed for the treatment of moderate to severe AD. Studies have shown that the main effect of Namenda® is to delay progression of some of the symptoms of moderate to severe AD. The medication may allow patients to maintain certain daily functions a little longer. For example, Namenda® may help a patient in the later stages of AD maintain his or her ability to go to the bathroom independently for several more months, a benefit for both patients and caregivers.

Namenda® is believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, may lead to brain cell death. Because NMDA antagonists work very differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination.

The FDA has also approved Aricept® for the treatment of moderate to severe AD.

Dosage and Side Effects

Doctors usually start patients at low drug doses and gradually increase the dosage based on how well a patient tolerates the drug. There is some evidence that certain patients may benefit from higher doses of the cholinesterase inhibitor medications. However, the higher the dose, the more likely are side effects. The recommended effective dosage of Namenda® is 20 mg/day after the patient has successfully tolerated lower doses. Some additional differences among these medications are summarized in the table on the other side.

Patients may be drug sensitive in other ways, and they should be monitored when a drug is started. Report any unusual symptoms to the prescribing doctor right away. It is important to follow the doctor's instructions when taking any medication, including vitamins and herbal supplements. Also, let the doctor know before adding or changing any medications.  

What potential new treatments are being researched?

The National Institute on Aging (NIA), part of the National Institutes of Health (NIH), is the lead Federal agency for AD research. NIA-supported scientists are testing a number of drugs to see if they prevent AD, slow the disease, or help reduce symptoms. Some ideas that seem promising turn out to have little or no benefit when they are carefully studied in a clinical trial. Researchers undertake clinical trials to learn whether treatments that appear promising in observational and animal studies actually are safe and effective in people.

Mild Cognitive Impairment. During the past several years, scientists have focused on a type of memory change called mild cognitive impairment (MCI), which is different from both AD and normal age-related memory change. People with MCI have ongoing memory problems, but they do not have other losses such as confusion, attention problems, and difficulty with language. The NIA-funded Memory Impairment Study compared donepezil (Aricept), vitamin E, or placebo in participants with MCI to see whether the drugs might delay or prevent progression to AD. The study found that the group with MCI taking the drug donepezil were at reduced risk of progressing to AD for the first 18 months of a 3-year study when compared with their counterparts on placebo. The reduced risk of progressing from MCI to a diagnosis of AD among participants on donepezil disappeared after 18 months, and by the end of the study, the probability of progressing to AD was the same in the two groups. Vitamin E had no effect at any time point in the study when compared with placebo.

Neuroimaging. Scientists are finding that damage to parts of the brain involved in memory, such as the hippocampus, can sometimes be seen on brain scans before symptoms of the disease occur. An NIA public-private partnership—the AD Neuroimaging Initiative (ADNI)—is a large study that will determine whether magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, or other imaging or biological markers, can see early AD changes or measure disease progression. The project is designed to help speed clinical trials and find new ways to determine the effectiveness of treatments.

AD Genetics. The NIA is sponsoring the AD Genetics Study to learn more about risk factor genes for late onset AD. To participate in this study, families with two or more living siblings diagnosed with AD should contact the National Cell Repository for AD (NCRAD) toll-free at 1-800-526-2839. Information may also be requested through the study’s website: http://ncrad.iu.edu.

Inflammation. There is evidence that inflammation in the brain may contribute to AD damage. Some studies have suggested that drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) might help slow the progression of AD, but clinical trials thus far have not demonstrated a benefit from these drugs. A clinical trial studying two of these drugs, rofecoxib (Vioxx) and naproxen (Aleve) showed that they did not delay the progression of AD in people who already have the disease. Another trial, testing whether the NSAIDs celecoxib (Celebrex) and naproxen could prevent AD in healthy older people at risk of the disease, has been suspended. However, investigators are continuing to follow the participants and are examining data regarding possible cardiovascular risk. Researchers are continuing to look for ways to test how other anti-inflammatory drugs might affect the development or progression of AD.

Antioxidants. Several years ago, a clinical trial showed that vitamin E slowed the progress of some consequences of AD by about 7 months. Additional studies are investigating whether antioxidants—vitamins E and C—can slow AD. Another clinical trial is examining whether vitamin E and/or selenium supplements can prevent AD or cognitive decline, and additional studies on other antioxidants are ongoing or being planned.

Ginkgo biloba. Early studies suggested that extracts from the leaves of the ginkgo biloba tree may be of some help in treating AD symptoms. There is no evidence yet that ginkgo biloba will cure or prevent AD, but scientists now are trying to find out in a clinical trial whether ginkgo biloba can delay cognitive decline or prevent dementia in older people.

Estrogen. Some studies have suggested that estrogen used by women to treat the symptoms of menopause also protects the brain. Experts also wondered whether using estrogen could reduce the risk of AD or slow the disease. Clinical trials to test estrogen, however, have not shown that estrogen can slow the progression of already diagnosed AD. And one study found that women over the age of 65 who used estrogen with a progestin were at greater risk of dementia, including AD, and that older women using only estrogen could also increase their chance of developing dementia.

Scientists believe that more research is needed to find out if estrogen may play some role in AD. They would like to know whether starting estrogen therapy around the time of menopause, rather than at age 65 or older, will protect memory or prevent AD.

For more information on recent estrogen study findings:

Menopause Companion, 2003 (PDF, 315K)

Understanding the Women's Health Initiative Study of Using Estrogen Alone, June 2004 (PDF, 30K)

What are Clinical Trials?

People with AD, those with MCI, or those with a family history of AD, who want to help scientists test possible treatments may be able to take part in clinical trials. Healthy people also can help scientists learn more about the brain and AD. The NIA maintains the AD Clinical Trials Database, which lists AD clinical trials sponsored by the Federal government and private companies. You also can sign up for e-mail alerts on new clinical trials as they are added to the database. Additional clinical trials information is available at www.clinicaltrials.gov.

Many of these studies are being done at NIA-supported Alzheimer's Disease Centers located throughout the United States. These centers carry out a wide range of research, including studies of the causes, diagnosis, treatment, and management of AD.

The NIA also supports the Alzheimer's Disease Cooperative Study (ADCS), a consortium of researchers at 109 sites in the U.S. and Canada conducting large-scale clinical trials of new approaches to treating and preventing AD. The ADCS is based at the University of California, San Diego.