Alzheimer's: "We Now Have Clear Targets"

Amgen's discovery of a key enzyme clears the way for further breakthroughs

In late October, Amgen Inc. announced the breakthrough discovery of one of the key triggers of Alzheimer's disease: an enzyme that sparks formation of the plaque deposits that clog the brains of its victims. The finding was reported one day before the annual meeting of the Society for Neuroscience, where, in three days, attendees heard about more advances in Alzheimer's than they had seen in decades. Elan Pharmaceuticals and SmithKline Beecham announced results of their work on a plaque-forming enzyme. Other scientists elaborated on the discovery only a few months ago of a different potential plaque trigger. And dozens of research teams reported findings on new drugs, diagnostic markers, and disease mechanisms. "This is a very, very exciting time in Alzheimer's research," says Dr. Dennis J. Selkoe, director of the Center for Neurologic Diseases at Brigham & Women's Hospital in Boston. "We now have clear targets" for drugs that inhibit the disease.

Finally. Although Alzheimer's disease was identified in 1906, there is still no effective long-term treatment for the degenerative brain disease. Even the latest discoveries offer no guarantee--the research was done on mice, not humans. And researchers are not sure if the plaque found in the brains of Alzheimer's victims is a cause of the disease or merely a consequence--in which case slowing its development would not bring a cure.

LAST FRONTIER. But there's no question that optimism is rife in the field. And the need could not be more dire. Alzheimer's disease strikes 10% of people over 65, and 50% of people over 85. Right now there are 4 million stricken Americans--including former President Ronald Reagan--and the cost of caring for them is $80 billion to $100 billion a year. Over the course of about 10 years, patients gradually lose their memory and ability to function, sinking into dementia and, finally, death. It is hard to diagnose, and there is no treatment that attacks its underlying causes.

For the drug industry, Alzheimer's disease is the last frontier. "There aren't many diseases that are completely untreated anymore," says Stephen M. Scala, a pharmaceutical analyst at S.G. Cowen Securities Corp. "There are probably 30 companies involved in some way in Alzheimer's." Scala estimates that the U.S. market for Alzheimer's drugs, totaling $550 million now, will reach $2.3 billion by 2003.

Despite massive research in recent years, there is only one drug currently approved in the U.S. that is specifically aimed at Alzheimer's: Pfizer Inc.'s Aricept, introduced in 1997. But Aricept and similar drugs seeking marketing approval offer only modest relief from symptoms, delaying the inevitable deterioration of the brain by 6 to 12 months.

No one yet knows why Alzheimer's strikes, but the brains of Alzheimer's victims, unlike patients with standard dementia, become riddled with what's called amyloid plaque--insoluble balls of protein that form in the regions responsible for memory, emotions, and thinking (see table). Later in the disease, tangles of protein develop inside brain cells. The plaque and tangles trigger inflammation and oxidation that steadily damage brain cells.

Most researchers are focusing on identifying the mechanisms that spark plaque buildup outside cells, because the internal tangles are much harder to decipher. The plaque is created by a protein fragment called beta-amyloid, a by-product of cell formation. Beta-amyloid is constantly being produced and cleared from the brain, but in Alzheimer's victims disposal is inhibited. Scientists believe the problem could lie with two enzymes involved in production of the protein. They have named the hypothetical enzymes beta-secretase and gamma-secretase.

SOLID DATA. On Oct. 22, Amgen caused waves of excitement in the Alzheimer's world when it announced, in the journal Science, that it had found beta-secretase. "It's immensely significant," says David B. Teplow, assistant professor of neurology at Harvard Medical School. "The evidence that this is beta-secretase is extremely solid."

And in April, Selkoe's lab at Harvard announced the discovery of a likely gamma-secretase candidate. This enzyme is so closely linked to gamma-secretase function, says Selkoe, that even if it isn't gamma secretase, blocking it could still slow plaque formation.

Many companies have been trying to stop plaque formation even without the specific targets in hand. Cowen's Scala says Bristol-Myers Squibb Co. and Eli Lilly & Co. will likely enter clinical trials next year with secretase inhibitors. Elan Pharmaceuticals is trying to block plaque formation by mobilizing the body's own immune system. Elan is seeking Food & Drug Administration approval for a vaccine made from beta-amyloid that significantly reduced plaque formation in genetically engineered mice.

Others are investigating anti-inflammatory drugs, to reduce the inflammation that accompanies plaque formation. Population studies have long noted that aspirin and other nonsteroidal anti-inflammatory drugs appear to reduce the risk of Alzheimer's by 50%. Now, both Merck & Co. and Monsanto Co. are in clinical trials for Alzheimer's with their COX-2 arthritis treatments, which are in the same category as aspirin but have fewer gastrointestinal side effects.

TRIALS IN PROGRESS. Clinicians are even more encouraged about the prospects for treatment with estrogen. Again, population studies show that women with low estrogen levels are at greater risk of developing Alzheimer's. That suggests that estrogen "may give the brain a better means to fight off the disease," says Dr. Claudia H. Kawas, clinical director of the Alzheimer's Research Center at Johns Hopkins University. She says more than 30 clinical trials are in progress to see if estrogen will delay onset of Alzheimer's disease.

"If you could delay the average age of onset by just five years, the number of new cases would be cut in half," says Steven H. Ferris, director of the Silberstein Aging & Dementia Research Center at New York University. For a disease this horrific, even small advances loom large.

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