Executive Health
Attacking Alzheimer's
Robert Langreth 04.21.08, 12:00 AM ET
Dennis Selkoe
The drug industry has bet heavily on one theory about the disease. What if that theory is wrong?
In 1906 a German psychiatrist described the puzzling case of a 56-year-old woman who had just died after years of progressive memory loss and hallucinations. An autopsy found her brain shriveled and filled with strange protein deposits. The disease, which took on the name of the psychiatrist, Alois Alzheimer, still mystifies doctors a century later. Researchers still debate its cause. And there are no treatments that stop its relentless and fatal course.
But that could be about to change. In a multibillion-dollar gamble, some of the world's biggest drug companies have begun final-stage trials of drugs that aim to slow or halt the progression of the devastating dementia. The products of over two decades of research, these drugs target the prime suspect in Alzheimer's disease, the telltale amyloid clumps spotted by the German doctor.
By clearing out those deposits or halting their production, researchers hope to slow brain cell death and alter the course of the illness. Even a drug that eased the decline only modestly could keep millions of patients out of nursing homes for years. "If we could keep people who are still functioning from having any further decline for five years--then they would probably die from something else," says Todd Golde, a neuroscientist at the Mayo Clinic, in Jacksonville, Fla. "The impact would be immeasurable."
Ultimately, doctors hope to use the disease-slowing drugs in conjunction with new brain-scanning methods being tested at General Electric (nyse: GE - news - people ) and elsewhere that will detect early signs of amyloid buildup. People with mild memory loss will get a brain scan to see if plaques are present. If they are, they'll then start the drugs right away to stop the disease in its tracks.
"Pretty much every pharmaceutical company in the world" is testing amyloid-busting drugs, says Menelas Pangalos, vice president for neuroscience research at the pharmaceutical firm Wyeth. Wyeth has spent over $500 million on Alzheimer's since 2001 and has four antiamyloid drugs in human testing. Its lead one is an antibody developed with Elan Corp. (nyse: ELN - news - people ) that has been shown to destroy 80% of the amyloid in the brains of affected mice.
Eli Lilly (nyse: LLY - news - people ) is hot on Wyeth's heels. Lilly has pursued Alzheimer's for nearly a quarter of a century. Its pill blocks an enzyme involved in amyloid production. Says Lilly's research chief, Steven Paul, "If amyloid isn't connected to the disease pathogenesis, God is playing a fairly mean trick on us." A dark horse in the race is Myriad Genetics (nasdaq: MYGN - news - people ), whose Flurizan pill aims to prevent the body from producing the most toxic form of amyloid.
But by focusing so heavily on amyloid, the drug industry is taking a big risk. Even after decades of research, the case that amyloid buildup is the main cause of the disease is hardly airtight. Studies have found that some people who die from other diseases, with no dementia, still have amyloid in their brains.
The trials "are based largely on theory and hope--and some rather considerable business considerations," says University of Southern California psychiatrist Lon Schneider, a consultant to several companies. "None of the drugs have shown evidence of efficacy yet." Geneticist John Hardy, one of the first to finger amyloid as a suspect, puts the odds at 50-50 that one of the antiamyloid drugs will work. "We are all on tenterhooks," he says.
Some researchers argue that amyloid is one of many factors in the disease and may not be the primary one for most people. "We may get rid of plaques, but it may not do anything," says John Trojanowski of the University of Pennsylvania.
Another potential culprit in the brains of Alzheimer's patients is neurofibrillary tangles. And other researchers are examining the role of a bad gene, apolipoprotein E e4. It can increase the risk of Alzheimer's disease tenfold.
Proponents of the amyloid theory "listen to each other and reinforce each other, and after a while it becomes more of a religious belief," says Zaven Khachaturian, former head of Alzheimer's research at the National Institutes of Health. He thinks companies should diversify--but until recently "if you spoke against amyloid it was like committing religious heresy."
The stakes could hardly be higher. Five million Americans suffer from Alzheimer's; the number could surge to 7.7 million by 2030. One in six women and one in ten men will get it. Existing drugs such as Aricept merely improve symptoms temporarily without slowing brain cell death. Drugs that slowed the decline would be surefire bestsellers.
Myriad will wrap up its final-stage trial any month now. Even more intensely awaited are the results of a second-stage trial of Wyeth's antibody, bapineuzumab. Both companies may reveal results this summer. Says Khachaturian, "If these trials work, it will open the floodgates. If they don't, we are back to square one."
Harvard neurologist Dennis Selkoe is a champion of the amyloid theory. A charismatic and convincing speaker, he has been touting it for two decades. "There's hardly a piece of evidence that doesn't support the idea that amyloid is the cause," he insists. "The naysayers say, 'People like you pollute the field,' and 'People are hoodwinked.' But [scientists] aren't that stupid. They vote with their test tubes, and they have put their test tubes into a huge number of experiments over this amyloid hypothesis."
Selkoe teamed up with venture capitalists in 1986 to found Athena Neurosciences, now part of Elan Corp. of Dublin, Ireland. He stayed at Harvard but serves as an Elan board member.
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