En español | New research appears to upend our current scientific understanding of the causes of Alzheimer’s disease, and may lead to a whole new approach to finding a cure for the devastating dementia.
The new theory gaining traction in the scientific community is that in Alzheimer’s the brain is destroyed not by sticky plaques — long held to be the culprit — but by floating clumps of protein. In fact, the sticky plaques that coat the brain cells of those with Alzheimer’s may be the body’s way of protecting against these deadly clumps — the way an oyster forms a pearl to protect against an irritating grain of sand, according to one researcher.
For the last 20 years, following the prevailing theory that sticky plaques cause Alzheimer’s disease, drug developers have been targeting that plaque in their search for a cure.
But experiments in mice and rats may prove to be the tipping point that takes that research in a new direction. Many scientists now believe the free-floating clumps of protein, rather than the sticky plaques, are the main players in the rogue process that attacks the brain.
“Plaques are no longer where the action is,” says Sam Gandy, M.D., of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine in New York.
Gandy’s work builds on several years of research that has been moving science toward this new theory. And if the theory is correct, then drugs that target plaques — as many of the most promising medications have done in the past few years — won’t help people who have the disease. It could even make them worse.
Gandy’s work with specially engineered mice, which developed Alzheimer’s though they had only clumps of the amyloid beta protein, and no plaques in their brains, “is the final experiment that’s making the whole field turn around,” says Andrew Dillin of the Salk Institute of California and the Howard Hughes Medical Institute.
While the development is exciting, William Thies, the Alzheimer’s Association’s chief medical officer, cautions that the leap from mice to men is a long one and that Gandy’s experiments need to be duplicated by other scientists in other labs before drug companies invest billions of dollars to create new medicines that target these clumps of proteins.
Still, this emerging science is especially important in light of statistics from the Alzheimer’s Association that say the number of Americans 65 and older who have the disease is likely to increase from more than 5 million today to 13 million 40 years from now as large numbers of boomers age.
Economic costs are expected to rise from $183 billion this year to more than $1 trillion by 2050. As part of the National Alzheimer’s Project Act, the government recently announced a goal of finding a way to prevent and treat Alzheimer’s disease by 2025. President Obama signed the law January 2011 and a final draft of a multi-agency plan is due to the Department of Health and Human Services in the spring.
A tangled web
Gandy’s study looked at the most basic science of the disease in a very different way. “Alzheimer’s seems to be caused by the buildup in the brain of clumps of material that are formed by the breakdown of protein,” Gandy says.
This protein, which normally occurs in the body, can change shape in several ways, he says. It can take a hairpin shape and form fibers called amyloid plaques, which are found in the brains of patients with Alzheimer’s. Or it can morph into free-floating protein clumps called oligomers, also found in the brains of those with Alzheimer’s disease.
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“These clumps ... seem to be more toxic to the brain,” Gandy says. He now thinks the oligomers, not plaques, cause the loss of memory and reason that characterize Alzheimer’s. Gandy and colleagues published their work in the Annals of Neurology in April 2010. Dillin, of the Salk Institute of California, started pursuing the same oligomer theory several years ago. Then the idea was so controversial, Dillin says, that some scientists would walk out of the room when he made his presentation at conferences. Now, he says, many of the top researchers in the field are convinced.
A plaque-free mouse
Alzheimer’s disease is characterized by two main elements — the sticky amyloid plaques that form outside the brain cells, and tangles of another protein, tau, that twist around the inside of the brain cells. Both are thought to play a role in the progression of the disease.
Scientists noticed the buildup of the sticky plaques in the brains of people with Alzheimer’s disease 100 years ago. And although there has been some debate, the prevailing science has held that sticky plaques and tau tangles cause Alzheimer’s.
Then, in 2004, scientists described mice that had no plaque but nevertheless showed signs of dementia. Other scientists showed that injecting rats with the oligomers caused memory loss. Another lab conducted an experiment to turn oligomers into plaques — they’re made of the same protein — and “when they did this gene trick, the mice got better, their memory improved,” Gandy says.
So Gandy and his colleague Michelle Ehrlich, M.D., also a professor at Mount Sinai, genetically engineered a new type of mice whose brains produce only oligomers but never brain plaques.
“Sam has done the most elegant experiments that really put the nail in the coffin” of the older, more widely accepted plaque theories, says Dillin.
Not only did these new mice lose their memories, but after their deaths the researchers found mice with the worst memory had the highest oligomer levels.
Oligomers “should be enemy number one,” agrees Rudolph Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital, an Alzheimer’s scientist and author of Decoding Darkness: The Search for the Genetic Cause for Alzheimer’s Disease.
Are plaques brain pearls?
The plaques and oligomers are originally formed from the same protein that is found throughout the body. These proteins break down naturally in the body throughout our lives. But Tanzi and others suspect that as the body ages, too many of these protein clumps, the oligomers, create a damaging buildup in the brain. They also may trigger the creation of tau tangles that gum up the brain’s signaling system.
The brain may try to remove the offending oligomers by forming plaques. Tanzi goes so far as to call the much-vilified plaques “brain pearls.” He says just as an oyster creates a pearl around a grain of sand to protect itself, plaques may serve as traps for microbes that are infecting the brain.
Researchers have found that some people who never had dementia nevertheless have brains coated in plaques. It may be, they theorize, that their brains were exceptionally good at converting the offending “sand” into “pearls.”
Drugs to watch
All this may help explain why research has shown that even though the drug bapineuzumab reduced plaque in the brain, the patients failed to improve. It could also explain the failure of the once-promising Alzhemed drug that discouraged the formation of brain plaques.
Dillin fears we may even discover that drugs designed to break down plaques may speed the disease’s progression.
“I think the plaques are a sign that your brain was trying to do something very beneficial for itself in the last stages of the disease,” he says. “If you go in and take these plaques apart, you’re going to make oligomers, and that could actually be worse.”
On the other hand, Dillin and others say too much protective plaque buildup in the brain may in fact be harmful, interfering with brain function.
Researchers in drug development say there are several Alzheimer’s medications in the pipeline that may work with the new theory.
Tanzi says he suspects the drugs that will work to prevent the disease or at least stop its progression will not entirely destroy the oligomers — he thinks they may play an important role in the brain — but will limit their production.
“Don’t expect to hit oligomers with a sledgehammer and still have the brain be OK,” he warns. Just as statins lower but don’t totally remove cholesterol in the body, he says, we need drugs that will “dial down” the production of the oligomers.
Tanzi is the cofounder of two companies, Neurogenetic Pharmaceutical and Prana Biotechnology, that are developing drugs to do just that.
“The best drugs are yet to come,” Tanzi says. “We’re starting to see some of them in early trials. It’s hard to be patient with a disease like this, but we’ve gone through the first wave of drug failures.”
He compares the first Alzheimer’s drugs to a 10-year-old shooting a soccer ball from midfield. “Now we’ve got a Division I college team driving down the field.”
Not so fast
However, Thies of the Alzheimer’s Association in Chicago is cautious about the new approach to this old disease. He says it’s too soon to eliminate plaques as a drug target. The results of three clinical drug trials “will give us a better handle” on the role of plaques.
Theis says that it could take 10 to 15 years to develop a drug that targets oligomers rather than plaques. There’s a lot of work to be done before this research translates into real help for Alzheimer’s patients, he stresses.
Still, Thies acknowledges that this type of basic science is “critical” and helps move researchers closer to a cure for Alzheimer’s disease.
“The fact is that without adequate support for this kind of basic science, there’s no hope,” he says.
Elizabeth Agnvall is a contributing editor with the AARP Bulletin.
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