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Alzheimer's: Searching for a Cure

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 treatment, 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). According to 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 researchers 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

Scientists continue to search for treatments 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 not yet have symptoms," Ferris predicts. And once new treatments come along to slow down the disease, those treatments 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

Scientists 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, according to 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 researchers 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 treatment.

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 researchers was able to diagnose AD in most cases by measuring the levels of these proteins in spinal fluid. These measurements, or biomarkers, may help scientists identify people 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 reported 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.