When molecular biologist Bob Vassar joined biotech giant Amgen in 1996, his mother was suffering from advanced-stage Alzheimer's disease. For years he'd taken care of her himself, since his father had died young. "Once she became incontinent I couldn't keep her at home any more," he recalls with more than a trace of guilt. In a nursing home, Vassar's mother slid rapidly downhill. In 1999, at age 78, she died-17 years after her diagnosis of Alzheimer's, which gradually but inexorably drains its victims of memory, judgment and reason.

Vassar was helpless to stop, or even slow, his mother's descent into dementia. But unlike most Alzheimer's caregivers, he was in a position to help others avoid her fate. At Amgen, in Thousand Oaks, CA, he designed and implemented an ingenious method for isolating the gene for an enzyme called beta-secretase-a key culprit in the disease. "It was a high-risk project, and there was no guarantee we could get it," says Vassar. In fact, his group individually tested 860,000 gene copies before finding beta-secretase and publishing the discovery in late 1999.

With success came hope. The U.S. Food and Drug Administration has approved three drugs for Alzheimer's disease, but these only temporarily improve brain function, without slowing or stopping progression of the disease. Other treatments are in advanced development (see "Bulging Pipeline" sidebar), but none has yet shown good long-term results. The discovery of beta-secretase, on the other hand, opens the possibility of halting the disease. "It's a huge leap forward," says Lennart Mucke, director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco. Possession of beta-secretase (discovered, almost simultaneously, by three other drug companies) has now set off a frenzied race to find and test a drug to block the enzyme and stop Alzheimer's in its tracks.

Blunting the Scissors

Although the cutting enzymes themselves proved maddeningly elusive, this model of Alzheimer's offered an obvious strategy for attacking the disease: block the enzymes and prevent the plaques. Since 1992, many drug companies have been looking for "secretase inhibitors," molecules that would block either gamma- or beta-secretase. One compound, a gamma-secretase inhibitor discovered at Bristol-Myers Squibb using mass screening techniques, entered early human trials in April 2000. "We're on the verge now of either preventing amyloid deposits from building up, inhibiting the production of amyloid, or actually being able to reverse plaque deposition," says Felsenstein, who leads Bristol-Myers Squibb's amyloid program. Other pharmaceutical firms-including DuPont, Merck, Elan and Eli Lilly-are testing gamma-secretase inhibitors as well, but haven't yet disclosed human trials.

But the drug-discovery process has been agonizingly slow. Just randomly sprinkling compounds on cells and measuring amyloid levels requires both time and luck to get a good hit. In fact, many drug companies ignored the secretases, since without the enzymes in hand, there's no way to know how specifically a compound is targeting them-making toxic side effects largely unpredictable.

Finding beta-secretase changes everything. Now medicinal chemists can design molecules to fit precisely into the enzyme's "active site." In theory, such drugs should be exquisitely specific, avoiding the worst side effects. Citron says Amgen is very excited about that possibility. The company has figured out the three-dimensional structure of the beta enzyme and is fashioning molecules to block its activity.