Posted on 04/13/2004 8:50:02 PM PDT by neverdem
Alzheimer's disease can seem unrelentingly grim. There is no cure, no known way to prevent the illness, and the benefits of current treatments are modest at best.
But in laboratories around the country, scientists are uncovering clues that may eventually — perhaps even in the next two decades — allow them to prevent, slow or even reverse the ruthless progression of the illness.
"Things are more hopeful than perhaps people think," Dr. Karen Duff of the Nathan Kline Institute of New York University said. "We are on the cusp of having something really useful."
That hope comes on the heels of disappointment. Aricept and other drugs to slow the disease's progress have not lived up to the public's high expectations.
But researchers are now turning in a new direction, testing whether other medications, some already on the market for other disorders, might head off Alzheimer's or keep it from becoming worse by acting on possible risk factors for the illness.
For example, several studies have suggested a link between Alzheimer's and cholesterol, which is produced by the brain, as well as by the liver, raising the possibility that statins, the drugs that lower cholesterol, might hold Alzheimer's at bay. Other researchers have hypothesized that medications that reduce inflammation, a hallmark of Alzheimer's in areas of the brain where cells are dying, might prove useful.
Still another idea is that Alzheimer's may be set off when someone who is predisposed to it receives another "hit" to the brain, for example from high blood pressure, reduced blood flow, a stroke or high cholesterol levels. If that is the case, a generation of middle-aged people who have had access to effective drugs for treating blood pressure and high cholesterol may already be receiving some protection.
Researchers have also found the first intimations that they may someday be able to reverse Alzheimer's destruction of the brain.
Dr. Norman Relkin, director of the Memory Disorders Program at Weill Medical College of Cornell, said studies testing ways to prevent or delay the disease would be completed in this decade.
"There is a high likelihood that one or more of them will be positive," Dr. Relkin said. "Do I believe we will have a disease modifying intervention before 2025? Absolutely."
If researchers had a dream about preventing Alzheimer's, it might go like this: A very safe drug is developed to treat a very common disease. Soon, millions are taking it, starting in middle age or even younger, when the terrible brain-cell death of Alzheimer's begins.
Amazingly, it turns out that this safe and popular drug has an unexpected benefit. It provides protection from Alzheimer's disease, preventing it altogether in some people, staving it off for years in others. The predictions that Alzheimer's cases will skyrocket as baby boomers reach old age never come true.
It is, of course, only a dream. But it is also not as far-fetched as it sounds, experts say. In the past few years, researchers have found evidence suggesting that statins, drugs taken by millions of Americans to lower cholesterol levels, may also protect against Alzheimer's.
The drugs, experts are quick to say, will never be a panacea.
"I have little hope that giving statins will eradicate Alzheimer's," Dr. Relkin said. "They are not a magic bullet."
Still, it is possible that statins may slow Alzheimer's or prevent some cases of it. Or at least, that is the hope of researchers who have found unexpected links between cholesterol and Alzheimer's.
The first hints emerged about a decade ago, when Alzheimer's researchers noticed a link between apo E, a protein that carries cholesterol in the blood, and the disease. Everyone inherits one of three versions of apo E. But people with the variant called apo E4 had an increased risk of Alzheimer's, the researchers found.
The finding was puzzling. There was no obvious reason that a protein that carried cholesterol in the blood should affect a disease that involved the accumulation of rough debris in the brain and the gradual death of brain cells. Yet the observation held. In study after study, apo E4 predisposed people to Alzheimer's.
Then, a few years ago, Dr. Benjamin Wolozin, a professor of pharmacology at the Loyola University Medical School in Maywood, Ill., got what he thought was a brilliant idea. He was doing laboratory experiments, following up on a report that cholesterol changed the way beta amyloid, a protein thought to be the main contributor to plaque in the brains of Alzheimer's patients, was processed.
It was pure laboratory research.
"From a medical standpoint, it was irrelevant," he said.
Then Dr. Wolozin realized that a similar experiment was already under way. Millions of people were taking statins, which lowered cholesterol levels. Were they also less likely to develop Alzheimer's?
Excited, Dr. Wolozin examined the records of 56,790 patients at three hospitals. The results exceeded his wildest hopes. Those who were taking statins had a 70 percent reduction in the prevalence of Alzheimer's.
Two journals rejected his paper, saying that he needed to learn statistics and that his results had to be a fluke. But he had a feeling that they were correct. He submitted the paper to The Archives of Neurology, which published it in 2000.
A few months later, Dr. Hershel Jick of the Boston University School of Medicine and his colleagues reported in The Lancet that they had compared 284 patients with Alzheimer's to 1,080 people with no dementia. In the patients who had taken statins, the scientists found, the risk of Alzheimer's was reduced by 70 percent.
Two other groups reproduced the observations. Other researchers found that statins protected genetically engineered mice that normally developed brain changes like those found in Alzheimer's.
The next step was to give statins to Alzheimer's patients and see whether the drugs affected the course of the disease.
But, Dr. Wolozin said, "the typical Alzheimer's thing happened — the data were mixed."
Despite the ambiguous findings, cholesterol does appear to be related to Alzheimer's, experts say. Several genes involved with cholesterol in addition to apo E4 also appear to affect the risk for Alzheimer's. Cholesterol, in fact, is so important to the brain, where it is used in nerve cell membranes, that the organ makes its own cholesterol independent of the liver, which produces the substance for the rest of the body.
"I hope the statins work," Dr. Wolozin said. "It may be that we just haven't figured out the right drugs or the right time to treat."
Other researchers are trying to see whether drugs that reduce inflammation can slow the progression of the disease. Studies have found that people who take aspirinlike anti-inflammatory drugs tend to have a lower incidence of Alzheimer's. But when Alzheimer's patients have taken anti-inflammatories, the study results have so far been disappointing. The disease was not slowed, but research is continuing.
Some scientists theorize that Alzheimer's may result from what they term multiple hits — someone on the edge of developing the disease may be pushed over by additional insults to the brain. The added hits could include, among other things, a stroke, high blood pressure or high cholesterol.
The theory makes sense, Alzheimer's experts say, because almost any injury to the brain increases the risk of the disease, and the risk factors for cardiovascular disease, which can decrease blood flow to the brain, increase the risk for Alzheimer's. If the multiple-hit theory is correct, detecting and treating high blood pressure or high cholesterol levels early may help prevent the illness.
Even if preventing Alzheimer's becomes a reality, some people will still develop it. For them, the goal is to find a way to reverse the progression, removing plaque in their brains and restoring the ability to think.
No one knows how to do this. But to neurologists' amazement, they have found hints that it may be possible. The glimmer of evidence comes from failed efforts to treat Alzheimer's disease by eliciting an immune response to the beta amyloid protein in plaques.
The idea was that an immunization might allow immune system cells to chew up the protein and remove it, clearing plaque from the brain. The immunizations worked beautifully in mice, and a few years ago, the manufacturers of the therapy, Elan Pharmaceuticals and Wyeth, began clinical trials in humans.
But when, in 2002, some patients developed severe inflammations of the brain and spinal cord, the trials were abruptly halted. The number of patients affected eventually grew to 18.
Elan and Wyeth continue to monitor the more than 300 other patients who received the immunizations, but they have stopped the treatment.
One researcher in that study was Dr. David G. Wilkinson, director of the Memory Assessment and Research Center at Moorgreen Hospital in Southampton, England, where 20 patients received immunizations.
When a woman died a year later of unrelated causes, Dr. Wilkinson wanted to examine her brain to find out whether the immunization had affected her Alzheimer's. His research team sliced the brain in thin sections and examined them under a microscope.
"It was really quite astonishing," Dr. Wilkinson said. The woman should have had a brain that was "absolutely peppered with amyloid plaque," but instead, huge areas were devoid of plaque.
"It was one of those, `We remember when we were all sitting around the microscope' days," he said.
Dr. Wilkinson published his finding last year in the journal Nature. Now, he says, four other patients from the trial have died, and their brains have been examined. One was from Portugal and the rest from the United States. In every case, the plaque was mostly gone.
In four of the five cases, the patients had had severe brain inflammations, raising the question of whether it was the immunization or the reaction to it that cleared the plaque. But the fifth patient, who did not develop inflammation, also had little plaque.
"This is the first concrete evidence of a disease-modifying strategy for Alzheimer's disease," Dr. Relkin said.
This particular immunization, he and others cautioned, is obviously not suitable for further study in patients. Wyeth and Elan are back in the clinic with what they hope will be a safer way to immunize. But for now, Dr. Wilkinson said, "we are a long way from a cure."
Nonetheless, he sees himself as an Alzheimer's optimist. "I think we will see a big, big reduction in Alzheimer's," Dr. Wilkinson said. "People shouldn't be so downbeat."
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