In the 15 years since Alzheimer's disease became a national priority for government-funded research, there has been little good news for its 4 million American sufferers. Even the Mar. 18 announcement that an advisory group to the Food & Drug Administration recommended approval of the first drug to treat the illness was a minor victory at best. Tacrine, made by Warner-Lambert Co., slows the mental decline in only a small percentage of patients, causes side effects such as liver damage in others, and does nothing to halt the destruction of brain cells that leads to Alzheimer's. A truly effective treatment awaits discovery of what causes that damage.

Quietly, in labs around the world, scientists are starting to close in on the answer. Since 1978, the National Institute on Aging (NIA) has doled out $800 million for Alzheimer's research. Drug companies have spent hundreds of millions more in pursuit of the $6 billion potential market they see for a genuinely effective drug. This vast research effort is revealing how complicated the illness is--and at the same time turning up discoveries that narrow the range of explanations for Alzheimer's.

In the past year, scientists have implicated three genes in the disease. They have also uncovered several biochemical defects that could cause the telltale devastation in the brain. Based on these discoveries, companies such as Athena Neurosciences, Scios, Merck, and Eli Lilly are hot on the trail of drugs that could correct the defects and halt the deadly ailment. "This field is going to take off like a rocket. All the pieces are there," says Zaven F. Khachaturian, chief of Alzheimer's Disease Research at the NIA, though he cautions that it could be five years or so before the first such therapies are available.

It's likely that there will be more than one way to attack the disease. That's because it's becoming increasingly clear that there are several ways to get Alzheimer's: Inherit one of at least four bad genes, have too little of several key brain chemicals, or at some point in life suffer damage to the tiny blood vessels that nourish the brain. "There are 20 million people worldwide who have Alzheimer's," says Dr. Dennis J. Selkoe, director of the Center for Neurologic Disease at Harvard's Brigham & Women's Hospital. "It makes sense that not all those cases would be caused by one gene defect." In fact, less than 10% of patients have a strong family history of the disease and get it while in their 40s or 50s. In the other 90% of cases, Alzheimer's strikes people with no known family history of the illness, usually after the age of 60.

Whether the disease is inherited or not, the brain of a deceased Alzheimer's victim shows the same pattern of damage. Areas involved in memory, emotion, and cognition are riddled with masses of proteins called plaques and tangles that literally gum up nerve cells. Now, researchers are trying to zero in on the common biochemical pathway that leads to the death of brain cells and find a way to intervene to stop the disease.

CAUSE OR EFFECT? Evidence is growing that the culprit is a sticky protein called beta amyloid that forms the plaques on the nerve endings of brain cells. Most researchers now agree that "the formation of amyloid is the final common pathway in Alzheimer's disease," says Dr. Richard J. Wurtman, director of the Clinical Research Center at Massachusetts Institute of Technology. But the scientists don't agree on whether beta amyloid is a cause of the disease or an effect. Some, such as Selkoe, believe too much beta amyloid in the brain triggers Alzheimer's. Others, including Dr. Allen D. Roses, professor of neurology at Duke University, think beta amyloid is a side effect of some other damage.

Beta amyloid is actually a peptide, or piece, of a larger protein called amyloid precursor protein (APP), found on the membrane of brain cells. In 1987, researchers found the gene that directs production of APP on chromosome 21, one of the 23 twisted pairs of DNA strands that hold the genetic instructions for life. Then, last December, Selkoe's group and another led by Dr. Steven G. Younkin at Case Western Reserve University found a defect in the APP gene that causes Alzheimer's in about 1% of all patients who inherit the disease. This defect causes the body to produce far too much amyloid protein.

That discovery gave a big boost to the amyloid-as-culprit theory. So did another piece of evidence. Selkoe's team, in conjunction with Athena Neurosciences Inc. in South San Francisco, and Younkin's group, working independently, found that lab-grown brain cells release amyloid protein from their membranes--without being damaged first. That was a blow to those who thought that it was impossible for beta amyloid to be produced by healthy, intact cells. "The conclusion is that if it comes out normally--not just from degenerating cells--then the problem with Alzheimer's disease is that too much is coming out," says Selkoe.

Cholesterol's role in heart disease is a good analogy for amyloid and Alz-

heimer's, says Dr. Ivan Lieberburg, vice-president at Athena Neuroscience, which was founded by Selkoe. Those with higher levels of beta amyloid may be at risk for Alzheimer's, just as those with high cholesterol levels are at risk for arteriosclerosis. The body may produce too much cholesterol, or the liver may not remove enough of it, or cells on the artery wall may be hypersensitive once it's deposited there. "We think the same thing is happening in Alzheimer's disease," says Lieberburg.

That's why there's a major shift in strategies for creating drugs against Alzheimer's. Athena; Scios in Mountain View, Calif.; and Cephalon in West Chester, Pa., are each developing agents that will block the key enzyme that snips beta amyloid from APP--the same way

Merck's top-selling Mevacor blocks a key step in cholesterol formation. Others are seeking drugs to remove beta amyloid from the body or protect nerve cells from damage.

The amyloid theory has gained many converts. Some 19 companies, including Merck, Bristol-Myers Squibb, Pfizer, and Upjohn, have started amyloid research. That's a welcome change, says Selkoe, who estimates that in the past 15 years, billions of dollars have been spent on cholinergic drugs such as Tacrine. Even now, a half-dozen similar drugs are in or nearing clinical trials. They lessen some effects of Alzheimer's by raising levels of acetylcholine, a key brain chemical that's depleted when neurons die. But they can be toxic, and they can't fend off the inevitable progress of the disease.

Still, drug companies haven't given up on cholinergic drugs in part because the beta amyloid theory doesn't answer all questions about the cause of Alz-

heimer's. "Most of us believe that dementia is caused by cells dying, but it's still controversial that amyloid actually kills cells," says neurologist John H. Growdon of Massachusetts General Hospital in Boston.

New research is beginning to dispel some of that controversy. In January, Dr. Harvey B. Pollard at the National Institute of Diabetes & Digestive & Kidney Diseases found that beta amyloid fragments can form channels that let calcium rush into cells. Too much calcium is toxic. Mark P. Mattson, a researcher at the University of Kentucky College of Medicine, found that if amyloid is added to healthy cells, it raises their calcium levels, making them more vulnerable to damage. And scientists at Sun Health Research Institute in Sun City, Ariz., have evidence that beta amyloid may cause chronic inflammation of the brain that could lead to a loss of function.

The next key question: What causes the buildup of beta amyloid? It's clear in a few cases that a mutation in the APP gene on chromosome 21 is to blame. Then, last October, researcher Gerard D. Schellenberg of the University of Washington in Seattle discovered that a gene on chromosome 14 is involved in half of all remaining cases of familial Alzheimer's. He says there are hints that the gene, which hasn't been isolated yet, helps regulate how APP is broken down. But chromosomes 21 and 14 don't seem to have a role in other inherited cases or in those afflicted after age 60.

Duke's Roses has found a gene on chromosome 19 that may be key to late-onset Alzheimer's. It directs the body to make a particular version, APOE-4, of a protein that helps move cholesterol in and out of cells. It can also grab hold of beta amyloid--and is found in plaques and tangles in victims' brains. People who carry this gene have "a risk factor for Alzheimer's," says Roses. He found the gene in 64% of those with the disease but in only 30% of the general population.

Roses believes APOE-4 causes formation of tangles--insoluble clumps of a protein called "tau" that collect in and damage nerve cells. "The amyloid plaque may be superfluous, a byproduct," he says. Selkoe counters that Roses' work fits the amyloid theory: "If something is wrong with APOE, it might not be able to bind with beta amyloid, and it would be available to accumulate as plaques."

SHOTGUN. Another clue about what might cause late-onset Alzheimer's came last October. Researchers at MIT and Massachusetts General Hospital in Boston found that low levels of the brain chemical acetylcholine, a common symptom of the disease, can lead to the formation of beta amyloid in lab-grown brain cells. Wurtman, who founded Interneuron Pharmaceutical Inc., a neuroscience company in Lexington, Mass., says this research could lead to a new drug strategy. Drugs such as Tacrine boost acetylcholine levels all over the body. So at doses high enough to counteract the underlying deficiency in the brain, they would be toxic to the heart, liver, and other regions of the brain.

Wurtman's group has zeroed in on a receptor, or docking site, for acetylcholine that is found only on cells in the learning areas of the brain. He says there are no drugs on the market that can target only this receptor but that his company is working on one. "My strong suspicion is that there will be ene in the very near future," says Wurtman.

Such bullish predictions are becoming more common among Alzheimer's researchers. "Things will go a lot faster," says the NIA's Khachaturian. "You have commitment from the government, many, many drug companies, and the scientific community to move at a very, very rapid pace." The hope for Alz-

heimer's patients and their families is that one day soon--perhaps in five years--researchers can offer them a treatment with real promise.

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