New Hope on Alzheimer's

By Frederic Golden

Striking with cruel randomness across an increasingly elderly population, Alzheimer's disease afflicts some 4 million Americans, most of them over the age of 65. They may range from a former President to a neighbor next door, but the ailment is always the same: it clutters the brain with tiny bits of protein, slowly robbing victims of their mental power until they are no longer able to do even the simplest chores or recognize their closest friends and kin. So far, medical science has been stymied, unable to treat the disease or slow its fatal progression.

Last week scientists offered what could be the first really strong ray of hope in their struggle against this relentless killer. In a report in the journal Science, the gene-splicing wizards at Amgen, one of biotechnology's most successful companies, announced that they had succeeded in identifying and isolating a long-sought enzyme--a so-called protease--that may play a key role in creating the biochemical chaos in the brain that causes Alzheimer's.

If so, the elusive enzyme could finally offer a target at which drug designers could aim their medications, just as they currently use protease inhibitors to block the activity of the AIDS virus. That potential target is called beta-secretase. It had long been postulated to act as a chemical scissors that helps snip away pieces of excess protein protruding from brain cells, thereby creating the debris that gathers into the toxic plaques called amyloid. The accumulation of these fibrous clumps in the brain of Alzheimer's patients is the likeliest reason for their inexorable decline.

As this protease theory of Alzheimer's became widely accepted a few years ago, it set off a scramble among drug companies to be the first to find the critical enzyme. And it's easy to see why. "You can take the protease, put it in a test tube and keep adding chemicals until you find one that inhibits the enzyme," says Dr. Rudy Tanzi, a Harvard neurologist whose lab unraveled key aspects of the genetics of Alzheimer's.

One of those who entered the race was molecular biologist Martin Citron. In 1997, shortly after he moved from Harvard to Amgen, in Thousand Oaks, Calif., he and his team began a long, painstaking elimination process by inserting active human genes, in strings of 100 at a time, into living bacterial cells. When the team found cells making more amyloid protein than might have been expected, it narrowed the strings to 20 genes and repeated the process. Finally, the Amgen team zeroed in on the single gene responsible for producing the extra amyloid. Having found the culprit, the researchers went on to "grow" the enzyme in their little bacterial factories and figure out exactly how it did its cutting.

The next step is to turn this laboratory triumph into a medication--one that can stop the enzyme without causing disastrous side effects. That won't be easy, and, as Citron points out, it won't happen overnight. Nor will the Amgen scientists lack for competition. Even as their Science paper appeared, other drugmakers indicated they were hot on the trail of the enzyme as well. And while Alzheimer's researchers offered the usual caveats, they seemed almost unanimously agreed that the identifying of the shadowy enzyme was not only a potential bonanza for drug companies but also the first really encouraging sign that there may yet be a light at the end of that long, dark tunnel called Alzheimer's.

--By Frederic Golden. With reporting by Dick Thompson/Washington

With reporting by Dick Thompson/Washington