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Alzheimer's Disease: Searching For A Cure

Alzheimer's Disease: Searching For A Cure Healthy nerve cells in the brain (neurons) have support structures called microtubules, which guide nutrients and molecules from the cell's body down to the ends and back. A special kind of protein, tau, makes the microtubules stable. Tau is changed chemically in people with Alzheimer's disease. It begins to pair with other threads of tau and they become tangled up together. When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in communication malfunctions between neurons and later in cell death.
It was 1997 when an alarm went off in Vivian Freed's head. She knew something was wrong with her 85-year old mother, who had always planned her trip to celebrate Thanksgiving with her children down to the last detail. But that year, she got the airline tickets for the wrong days. Freed also found out that her mother had been missing doctors' appointments and social engagements, so she flew from her home in Rockville, Md., to her mother's home in Florida to check on her.

"Everything that she had done perfectly before was a mess," says Freed. The bills weren't paid, and the medications that her mother had been giving to her ailing father weren't right. "We realized we needed to do something," says Freed, after a doctor diagnosed her mother with Alzheimer's disease.

Freed's sister, Annette Heller, later "adult-napped" her parents and moved them to Maryland under the pretense of just visiting." They didn't really notice that she was packing up more things than they would need for just a visit," says Freed.

Her parents were fiercely independent and would have objected to moving. "It would have been much nicer to give them closure, but it wasn't possible," Freed says.

Not long after Freed moved her parents into an assisted living facility in Maryland, her father passed away. "The day after he died, Mom remembered what happened, but never did again," she says. "Mom kept asking, 'Where's Daddy?'".

As her mother's mental and physical health continued to deteriorate, Freed moved her into a small group home where she got 24-hour care. Alzheimer's disease, along with worsening vision, prevented her mother from recognizing Freed. "It was a very slow demise," she says. Her mother died at age 90 in 2002.

"Ultimately, Alzheimer's is fatal," says William Thies, Ph.D., vice president of medical and scientific affairs at the Alzheimer's Association in Chicago. "Until research provides the answers, Alzheimer's will continue to exact a terrible toll on those with the disease, as well as on their families, friends and caregivers".

But an explosion of Alzheimer's research in the last 10 years and its continuing momentum hold out hope for potential preventions and treatments for this devastating disease.

Rising Numbers
Health care costs for the roughly 4.5 million Americans with Alzheimer's disease (AD) exceed $100 billion a year, according to the Alzheimer's Association. As baby boomers age during the next few decades, the number of victims and the dollar costs of care are expected to almost quadruple.

As age increases, so does the risk of getting AD. For each five-year age group beyond 65, the percentage of people with AD doubles, according to the National Institute on Aging (NIA). Nearly half of those over age 85 have it. A small number are diagnosed with "early-onset Alzheimer's," which can strike people in their 30s, but most AD cases are among older people. A person with AD lives an average of eight years after the onset of symptoms, but some live as long as 20 years.

A Disease of the Brain
AD is a brain disorder that occurs gradually. It starts with mild memory loss, changes in personality and behavior, and a decline in thinking abilities (cognition). It progresses to loss of speech and movement, then total incapacitation and eventually death. It is normal for memory to decline and the ability to absorb complex information to slow as people get older, but AD is not a part of normal aging.

Researchers aren't exactly sure what causes AD, but they do know that people with the disease have an abundance of two abnormal structures in the brain: plaques and tangles. Plaques are dense, sticky substances made up of accumulations of a protein called beta-amyloid. Tangles are twisted fibers caused by changes in a protein called tau. The beta-amyloid plaques reside in the spaces between the billions of nerve cells, or neurons, in the brain, and the neurofibrillary tangles clump together inside the neurons. Plaques and tangles block the normal transport of the electrical messages between the neurons that enable us to think, remember, talk and move. As AD progresses, nerve cells die, the brain shrinks, and the ability to function deteriorates.

Treating the Symptoms
There is no cure for AD, but there are drugs to treat some of the symptoms. The Food and Drug Administration has approved four prescription drugs for people with mild-to-moderate AD: Cognex (tacrine), Aricept (donepezil), Exelon (rivastigmine), and Reminyl (galantamine). "All of them work by the same mechanism," says Russell Katz, M.D., director of the FDA's Division of Neuropharmacological Drug Products. The drugs increase the level in the brain of acetylcholine--a chemical that nerves use to communicate with each other. "People with AD are deficient in this neurotransmitter, and the drugs work by inhibiting an enzyme called cholinesterase that breaks down the acetylcholine," says Katz. "These cholinesterase inhibitors have an effect on the symptoms, but we have no evidence that they have any effect on the underlying progression of the disease. During therapy, as far as we know, the nerve cells are still dying and the various plaques and tangles are still forming".

"There's healthy debate about whether these drugs actually affect the course of the illness," says Trey Sunderland, M.D., chief of the Geriatric Psychiatry Branch of the National Institute of Mental Health (NIMH). As per the data, says Sunderland, "If people are on the cholinesterase inhibitors, they tend to go to nursing homes later than people who are not on the inhibitors." Some scientists have reported a delay of up to 22 months in going to nursing homes, he adds.

Another drug, Namenda (memantine), is approved to treat people with moderate-to-severe Alzheimer's disease. This drug is thought to work by blocking the action of glutamate, a brain chemical that may be overactive in people with AD.

Treating the Disease
Researchers continue to search for therapys to slow the progress of AD and to hold the disease off as long as possible. "If you could delay the onset of symptoms by five years, the total number of new cases projected into the future would be cut in half," says Steven Ferris, Ph.D., director of the Alzheimer's Disease Center at the New York University School of Medicine. "Within the next five to 10 years, we will at least be able to slow down the disease in people who already have symptoms and do a much better job at identifying people at high risk of getting Alzheimer's who do still not have symptoms," Ferris predicts. And once new therapys come along to slow down the disease, those therapys may be given to people at high risk, he adds, so a growing number of people will live longer but not long enough to get AD.

Diagnosing Alzheimer's
Researchers are uncovering clues to better diagnose the disease and to determine who is at risk. "It is my hope that in time for the baby boomers, there will be both a prognostic test, as well as at least one therapeutic strategy," says Sunderland. "Both prognostic and therapeutic options are needed. If you had a preventative drug that potentially had toxicity associated with it, you wouldn't want to give it to everybody--only the subpopulation at greatest risk".

Today, AD can be diagnosed conclusively only by examining the brain after death. But physicians can make a probable diagnosis on living patients by taking a complete medical history, administering neurological and psychological tests, and doing a physical exam, blood and urine laboratory tests, and a brain-imaging scan. Once symptoms begin, the disease can be diagnosed with up to 90 percent accuracy by experienced physicians, as per the NIA.

But do people start getting AD before symptoms show themselves? "That's the big question in Alzheimer's disease: When does it really begin?" says Sunderland. No one knows for sure, he says, but research "suggests that the illness may predate clinical symptoms by years and maybe decades".

Advances in neuroimaging--taking pictures of the brain to measure its structure and activity--may allow scientists to see the accumulation of plaques and tangles at various points in time. Neuroimaging may one day prove useful in monitoring the progression of the disease and assessing people's responses to drug therapy.

Another early indication of AD could be found in a person's spinal fluid, which, like the brain, carries beta-amyloid and tau proteins. In a study at the NIMH, Sunderland's team of scientists was able to diagnose AD in most cases by measuring the levels of these proteins in spinal fluid. These measurements, or biomarkers, may help researchers identify people who are at risk for AD, says Sunderland. "By establishing a person's baseline and tracking levels over time, we might be able to interpret gradual changes as a sign that he or she is developing the disorder." Sunderland's study, which included physical examination of more than 200 participants and an analysis of over 50 similar studies, is published in the April 23, 2003, issue of the Journal of the American Medical Association (JAMA). While work in this area is currently investigational in nature, spinal fluid testing may become a valuable routine diagnostic tool in the future.

Delaying the Disease
Some studies hint that a variety of existing drugs and supplements may be useful in delaying AD or stopping its progression. These studies are preliminary, and their findings would need to be demonstrated in adequately designed and conducted studies before their conclusions can be considered proven, says Katz.

Cholesterol-lowering drugs, anti-inflammatory drugs, antioxidants, and estrogen are some of the substances that have been studied, but study results have been conflicting. These studies don't prove causation, warns Thies of the Alzheimer's Association. "All they really tell us is it's a good place to start doing clinical trials." And scientists are doing just that.

The Heart and Head Connection
Studies have shown a link between known risk factors for heart disease--high blood pressure, high cholesterol levels, and diets high in saturated fats and trans fats--and an increased risk for AD. There is also evidence that an elevated level of homocysteine, an amino acid in the blood, presents a risk for both heart disease and AD. Further, taking cholesterol-lowering drugs (statins) is associated with a lower occurrence of AD.

"What is good for the heart may be good for the head," says Thies, and healthy lifestyle behaviors such as exercising, eating healthily, and managing blood pressure and cholesterol may be of value in protecting people from AD.

Large-scale clinical trials are being conducted to clarify the link between cardiovascular risk factors and AD. In addition to statins, substances being tested for slowing and preventing AD are folate (a form of B vitamin) and vitamins B6 and B12, which may lower homocysteine levels.

Anti-inflammatory Drugs
People who take large doses of non-steroidal anti-inflammatory drugs (NSAIDs), usually used to reduce joint inflammation and pain, have a reduced likelihood of developing AD, as per some studies. NSAIDs, which include over-the-counter aspirin and ibuprofen, as well as some prescription drugs, such as Celebrex (celecoxib), may reduce the inflammation in the brain associated with AD.

None of the studies performed with the anti-inflammatory drugs to date are definitive, cautions Katz, and these drugs would need to be studied in scientifically rigorous trials before the effects of these drugs on AD could be accepted. One of these trials, the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT), was launched in 2001 to test the effectiveness of some NSAIDs in preventing AD. The study of more than 2,500 healthy participants age 70 and over is sponsored by the NIA and is scheduled to run between five and seven years.

Scientists are also looking at antioxidants to possibly prevent cognitive decline. Antioxidants, such as vitamin E, vitamin C and carotene, may help break down "free radicals"--cell-damaging compounds that are byproducts of normally functioning cells. The natural defenses of cells protect against these compounds, but these protective mechanisms decline as a person ages.

Some study results have suggested that antioxidants may protect against cell damage and lessen the likelihood of getting AD. But a four-year study of nearly 1,000 older people conducted at Columbia University found that consuming carotenes or vitamins C and E either through the diet or by supplements did not decrease the risk of developing AD. "This large-scale study is at variance with earlier indications that these supplements are effective as a therapy for Alzheimer's," says Thies. "This tells us that more work needs to be done before we completely understand the value of these agents." The results of this study are reported in the February 2003 issue of Archives of Neurology.

"There are virtually shelf-fuls of compounds capable of acting in an antioxidant fashion," says Thies. One of these, Ginkgo biloba, used for thousands of years in Chinese herbal medicine, has been shown in a small study to result in a modest improvement in cognition, social behavior and performing activities of daily living, such as dressing and eating. A larger study (about 3,000 participants) funded by the National Institutes of Health (NIH) is currently investigating the effectiveness of Ginkgo in preventing or delaying cognitive decline in elderly adults.

The FDA cautions consumers that some supplements may interact with prescription and over-the-counter medicines and cause serious harm. Check with your doctor or health care provider before taking any dietary supplement, including herbs.

Several epidemiological studies have linked the female hormone estrogen to improved memory and possible delay or prevention of AD in women. But a large, long-term clinical trial sponsored by the NIH has provided evidence to the contrary. In the trial, part of the Women's Health Initiative Memory Study (WHIMS), women 65 and over taking estrogen combined with another hormone, progestin, had twice the rate of dementia, including AD, than those women not taking the hormones. The study, reported in the May 28, 2003, issue of JAMA, also found that the hormone combination did not protect against the development of mild cognitive impairment, a form of mental decline less severe than dementia.

New Drug Development
New drugs are emerging from the basic science laboratories and moving toward testing in human trials. "The ones furthest along are based on the amyloid hypothesis," says Thies. The hypothesis is that AD starts with the accumulation of amyloid plaques, and that limiting this accumulation will change the progress of AD.

Researchers have isolated enzymes called secretases, which are thought to lead to the formation of beta-amyloid. Secretases are categorized as proteases, the same type of enzymes that are targeted by protease inhibitors to treat AIDS. Drugs called secretase inhibitors are being developed to block beta-amyloid formation, and some of these drugs are now being tested.

Another approach to plaque attack is to stimulate the body's immune system to destroy the beta-amyloid. Researchers developed a vaccine that put amyloid into the blood in the hopes of making antibodies to destroy the plaques. The vaccine was successful in transgenic mice--special mice that were injected with human genes that caused them to develop AD-like plaques. But when tested in a human trial, some people showed inflammation of the brain (encephalitis). Further vaccination was stopped, but study participants continue to be followed. Eventhough this particular vaccine may be disappointing, a number of researchers think that the strategy of fighting AD by stimulating the immune system still remains an important potential avenue to slow or prevent the disease.

"We are still searching for the sequence of events where we can intervene and cure the disease without causing harm," says Marcelle Morrison-Bogorad, Ph.D., associate director of the NIA's Neuroscience and Neuropsychology of Aging Program. Morrison-Bogorad notes that researchers may someday be able to inject a substance into the blood to draw amyloid from cerebral spinal fluid and the brain. "This can happen in transgenic mice--we don't know whether it happens in humans yet".

Risk Factors
The two biggest risk factors for getting AD are age and genetics, neither of which is in our control, says Thies. Researchers have identified several genes that play a role in early-onset AD, a rare form of the disease that strikes people as young as in their 30s. For late-onset AD, defined as showing symptoms after age 65, a gene that produces a protein called apolipoprotein E (ApoE) appears to play a role. The gene comes in several forms, or alleles. Having the ApoE4 allele increases the risk for getting AD, as per the NIA.

About 40 percent of people with AD have the ApoE4 allele, but inheriting it doesn't mean a person will definitely get AD. Some people with the gene never get the disease, and some without it do develop AD. Once scientists know more about how genetics affects AD, people could be genetically screened and then treated based on their genetic factors.

Some studies have shown that participating in mentally stimulating activities, such as reading books, doing crossword puzzles, or going to museums, may be associated with a reduced risk of AD. Scientists speculate that repetition might improve certain cognitive skills, making them less susceptible to brain damage.

This "use-it-or-lose-it" theory may have value, but further study is needed, says Morrison-Bogorad. AD may actually cause people to stop doing mentally challenging activities because the disease makes it harder to do them, she says. "It's impossible to tease out the cause and effect in these studies. We can only say it's correlative--not causal." Morrison-Bogorad does encourage mental activity. "It keeps you nimble--whether it helps prevent Alzheimer's, we don't know".

By Linda Bren
Linda Bren is a staff writer for FDA Consumer.

Did you know?
It was 1997 when an alarm went off in Vivian Freed's head. She knew something was wrong with her 85-year old mother, who had always planned her trip to celebrate Thanksgiving with her children down to the last detail. But that year, she got the airline tickets for the wrong days. Freed also found out that her mother had been missing doctors' appointments and social engagements, so she flew from her home in Rockville, Md., to her mother's home in Florida to check on her. Alzheimer's Disease: Searching For A Cure

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