Unraveling Alzheimer's

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Ever since 1906, when German physician Alois Alzheimer described the degenerative brain disorder that bears his name, doctors have argued about what exactly causes the disease. Dr. Alzheimer carefully noted two main features of the autopsied brains of his patients: the dense clumps, or plaques, of protein that showed up where nerve cells should have been and the tortured tangles that many of the neurons had become. But whether the plaques or the tangles triggered the illness or they were both just the most visible effects of some other, more obscure process no one could say for sure.

Now the century-old mystery is on the verge of being solved. As researchers, physicians and caregivers gather in Washington next week for the World Alzheimer Congress, the scientists who favor plaques as the culprit are getting a first crack at proving their hypothesis. Thanks to a series of discoveries--some of which have been made only in the past couple of months--they should soon be able to demonstrate once and for all whether getting rid of plaques is the most important step in halting the progression of Alzheimer's disease. They've already started preliminary clinical trials in human volunteers of the first anti-Alzheimer's compounds designed to treat the cause, and not just the symptoms, of the disease.

The most straightforward approach to fighting Alzheimer's plaques is to target their main ingredient, a protein called beta amyloid. Last summer scientists from Elan Pharmaceuticals, a biotech firm located in Ireland, reported that they had developed a vaccine that could shrink the plaques--at least in mice. Here the idea is to prime the immune system to treat amyloid proteins just as it would any foreign invader and target them for destruction. The concept is somewhat counterintuitive, since most researchers believe that at least part of the damage in Alzheimer's disease is caused by the immune system's overreaction to the presence of plaques and tangles. But the idea was so simple and the animal studies were so encouraging that Elan researchers decided to try it out on people.

Initial results of a small safety trial will be reported at the Alzheimer's conference next week. If all goes well, Elan will undertake further studies to determine what positive effects, if any, the potential treatment might have on the brain.

Another approach, favored by several large pharmaceutical companies, is to try to block the body's production of amyloid proteins. It turns out that everyone makes beta amyloid throughout his brain and body (more on that later). But people who, for genetic reasons, tend to get Alzheimer's at an early age--in their 40s or 50s--seem to shape the protein into a stickier version that is more likely to clump together. By inhibiting an enzyme called gamma secretase, which facilitates amyloid production, researchers hope to push amyloid production so low that no new plaques will form.

In one of those funny little twists so common in biochemistry, scientists knew what gamma secretase did before they knew what it looked like. They knew, for example, that it belonged to a group of enzymes called proteases. But last month, when several different labs reported almost definitive evidence of the enzyme's identity, it looked nothing like any other protease. That was a big surprise, says Dr. Dennis Selkoe of Brigham and Women's Hospital. As it happens, however, drug companies have become expert over the years in developing protease inhibitors for AIDS patients, and they were able to move quickly.

In March, Bristol-Myers Squibb injected a handful of healthy volunteers with a compound that their lab studies indicated should inhibit the gamma-secretase enzyme. So far, they have been encouraged by the results. But it's still too early to tell whether these first subjects, who don't have Alzheimer's disease, are getting a high enough dose to make any difference.

One potential drawback to blocking gamma secretase is that no one is quite sure what its natural role in the body might be. There's already some evidence that gamma secretase is crucial to the normal development of blood cells, for example. So most pharmaceuticals researchers are aiming for a 30% to 40% reduction in its activity in the hopes that that won't upset too many other important bodily functions.

Even if blocking gamma secretase turns out to be a good idea, there's no guarantee that it will help everyone with Alzheimer's. While the enzyme clearly plays a role in the 10% of cases that develop in middle age, it's not so obvious that blocking gamma secretase will do any good for the 90% of Alzheimer's patients who develop symptoms after age 65. In their case, the problem may not be an overabundant supply of amyloid protein. Their body simply may not do a very good job of getting rid of it. Treating older patients with Alzheimer's disease could require an entirely different approach.

Meanwhile, some scientists are still trying to figure out how neuronal tangles fit into the degenerative process. For years their work was hampered by the fact that they could not re-create tangles in laboratory mice. Then, in the 1990s, researchers isolated the genetic mutations that cause frontotemporal dementia, a neurological disorder that is similar to Alzheimer's disease but that also interferes with muscle coordination. Intriguingly, the patients' brains were riddled with tangles but not amyloid plaques.

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