The brains of the mice that Bradley Hyman keeps in his sprawling lab at an old naval base in Boston offer a window, literally and figuratively, into the mysterious damage that causes Alzheimer's disease. When each mouse reaches a few months of age, one of the lab workers carefully creates an opening in its skull and places a tiny glass window over the hole. Day after day, week after week, a powerful microscope is trained on the brain, searching for ugly clumps of sticky protein fragments like those that litter the brains of elderly people who have died of Alzheimer's. "It's like time-lapse photography," says Hyman, director of the Massachusetts Alzheimer's Disease Research Center at Harvard Medical School. When the ugly plaques appear—and they always do, as the mice carry genes engineered to produce them—nearby brain cells begin to wither and die, interrupting the flow of information. Next, waves of cells die off.
Hyman's microscope is one of several new technologies that promise to revolutionize the struggle to understand and beat Alzheimer's, which now afflicts more than 5 million Americans. Worldwide, a staggering 1 percent of all economic output is spent caring for and treating people with it and other types of dementia, according to Alzheimer's Disease International, the umbrella group of Alzheimer's associations around the globe. Meanwhile, just four drugs have been approved by the Food and Drug Administration to battle the disease, and all address symptoms only, not the poorly understood causes. Over the past decade, billions of dollars have been poured into researching drug after initially-promising drug, and nearly all have been disappointing in large clinical trials.
"When you can watch the brain over time, we see now, we didn't have the details right," says Hyman, who holds out great hope that his microscope studies will help correct that. One assumption has been that the plaques themselves, accretions of a protein fragment called beta amyloid, harm the brain. Instead, it appears that the individual sticky strands that eventually form the plaques damage neurons, and that the plaques are a sign of a brain long under siege.
For years, researchers have debated whether the brains of people who develop Alzheimer's produce excess beta amyloid or they're simply bad at clearing it. In December, researchers at Washington University School of Medicine in St. Louis provided strong evidence for the latter theory. They measured radioactively labeled beta amyloid visible in the spinal fluid of healthy older adults and people with Alzheimer's. Both groups appeared to produce the same amount, but the ill individuals cleared the substance from their brains into their spinal fluid at a rate about 30 percent slower. Moreover, since autopsy studies find that some people with no cognitive symptoms of Alzheimer's carry a substantial plaque load, the body may possess a varying capacity to withstand beta amyloid's assault.
Following on the success of periodic cholesterol testing, which has revolutionized heart care, researchers are experimenting with measuring beta amyloid via brain scans, spinal taps, and blood tests. Early results offer hope that, someday, physicians will be able to screen the middle-aged for the hallmarks of pre-Alzheimer's. "It's critical to identify people at risk," says Reisa Sperling, who is using brain PET scans of beta amyloid at Brigham and Women's Hospital in Boston to study the impact in people who are not showing symptoms. She's concerned that right now drug treatment starts five or 10 years too late. An FDA advisory committee recommended in January that the agency approve a PET scan that could be helpful in diagnosing people who already have the plaques.
Of course, without effective drugs, early detection offers little solace. Most of the recently failed drugs aimed to interrupt production of beta amyloid by blocking the enzyme that produces it. However, researchers have opened a new front in the battle, targeting the synapses between neurons, which new research shows may be the first structures to deteriorate. Another approach, based on the theory that the body must have natural defenses if most people don't get Alzheimer's, seeks to train the immune system to attack beta amyloid. But all of the new drugs have been given to patients who already show cognitive symptoms. Adrian Ivinson, director of the Harvard NeuroDiscovery Center, which focuses on degenerative brain diseases, thinks some of the failed drugs should be retested in asymptomatic individuals who show beta amyloid on brain scans or in spinal fluid tests. "The implication of all this work is we have to get [the drugs] into people before they're patients," he says. "They have a silent disease."
What about prevention? There is accumulating evidence that exercise, eating fish or other sources of omega-3 fatty acids, and remaining intellectually and socially engaged throughout life reduce the risk of Alzheimer's. But last year a panel assembled by the National Institutes of Health concluded that the evidence on lifestyle interventions is inconsistent and inconclusive, pretty much across the board. "There are suggestions that some things might be effective, but there isn't strong, high-grade evidence for any of them," says Neil Buckholtz, chief of the dementias of aging branch of the National Institute on Aging. The NIA is now running several large studies to see if exercise, diet, or social or intellectual engagement will reduce risk.
Having had a stroke substantially raises the odds of Alzheimer's, as does having diabetes. But the biggest known risk factor is one people can do nothing about: a family history of the disease. People carrying one copy of variations in a gene called APOE are at about a threefold risk, while those carrying two copies have a whopping 12-fold risk. But it appears possible now that many genes, perhaps even a hundred, may each confer a tiny increased risk of developing Alzheimer's. Still, Rudy Tanzi, an Alzheimer's geneticist at Harvard Medical School, is hopeful that by 2020, a screen of a person's genome will reliably estimate his or her risk of developing the disease. Ideally, the people at highest risk will then have scans or spinal fluid or blood tests regularly to detect accumulating beta amyloid. Once it is seen, they'll begin taking the equivalent of a "statin for the brain" to reduce the load. And Alzheimer's will become as preventable as heart disease is today.
Hyman's microscope is one of several new technologies that promise to revolutionize the struggle to understand and beat Alzheimer's, which now afflicts more than 5 million Americans. Worldwide, a staggering 1 percent of all economic output is spent caring for and treating people with it and other types of dementia, according to Alzheimer's Disease International, the umbrella group of Alzheimer's associations around the globe. Meanwhile, just four drugs have been approved by the Food and Drug Administration to battle the disease, and all address symptoms only, not the poorly understood causes. Over the past decade, billions of dollars have been poured into researching drug after initially-promising drug, and nearly all have been disappointing in large clinical trials.
"When you can watch the brain over time, we see now, we didn't have the details right," says Hyman, who holds out great hope that his microscope studies will help correct that. One assumption has been that the plaques themselves, accretions of a protein fragment called beta amyloid, harm the brain. Instead, it appears that the individual sticky strands that eventually form the plaques damage neurons, and that the plaques are a sign of a brain long under siege.
For years, researchers have debated whether the brains of people who develop Alzheimer's produce excess beta amyloid or they're simply bad at clearing it. In December, researchers at Washington University School of Medicine in St. Louis provided strong evidence for the latter theory. They measured radioactively labeled beta amyloid visible in the spinal fluid of healthy older adults and people with Alzheimer's. Both groups appeared to produce the same amount, but the ill individuals cleared the substance from their brains into their spinal fluid at a rate about 30 percent slower. Moreover, since autopsy studies find that some people with no cognitive symptoms of Alzheimer's carry a substantial plaque load, the body may possess a varying capacity to withstand beta amyloid's assault.
Following on the success of periodic cholesterol testing, which has revolutionized heart care, researchers are experimenting with measuring beta amyloid via brain scans, spinal taps, and blood tests. Early results offer hope that, someday, physicians will be able to screen the middle-aged for the hallmarks of pre-Alzheimer's. "It's critical to identify people at risk," says Reisa Sperling, who is using brain PET scans of beta amyloid at Brigham and Women's Hospital in Boston to study the impact in people who are not showing symptoms. She's concerned that right now drug treatment starts five or 10 years too late. An FDA advisory committee recommended in January that the agency approve a PET scan that could be helpful in diagnosing people who already have the plaques.
Of course, without effective drugs, early detection offers little solace. Most of the recently failed drugs aimed to interrupt production of beta amyloid by blocking the enzyme that produces it. However, researchers have opened a new front in the battle, targeting the synapses between neurons, which new research shows may be the first structures to deteriorate. Another approach, based on the theory that the body must have natural defenses if most people don't get Alzheimer's, seeks to train the immune system to attack beta amyloid. But all of the new drugs have been given to patients who already show cognitive symptoms. Adrian Ivinson, director of the Harvard NeuroDiscovery Center, which focuses on degenerative brain diseases, thinks some of the failed drugs should be retested in asymptomatic individuals who show beta amyloid on brain scans or in spinal fluid tests. "The implication of all this work is we have to get [the drugs] into people before they're patients," he says. "They have a silent disease."
What about prevention? There is accumulating evidence that exercise, eating fish or other sources of omega-3 fatty acids, and remaining intellectually and socially engaged throughout life reduce the risk of Alzheimer's. But last year a panel assembled by the National Institutes of Health concluded that the evidence on lifestyle interventions is inconsistent and inconclusive, pretty much across the board. "There are suggestions that some things might be effective, but there isn't strong, high-grade evidence for any of them," says Neil Buckholtz, chief of the dementias of aging branch of the National Institute on Aging. The NIA is now running several large studies to see if exercise, diet, or social or intellectual engagement will reduce risk.
Having had a stroke substantially raises the odds of Alzheimer's, as does having diabetes. But the biggest known risk factor is one people can do nothing about: a family history of the disease. People carrying one copy of variations in a gene called APOE are at about a threefold risk, while those carrying two copies have a whopping 12-fold risk. But it appears possible now that many genes, perhaps even a hundred, may each confer a tiny increased risk of developing Alzheimer's. Still, Rudy Tanzi, an Alzheimer's geneticist at Harvard Medical School, is hopeful that by 2020, a screen of a person's genome will reliably estimate his or her risk of developing the disease. Ideally, the people at highest risk will then have scans or spinal fluid or blood tests regularly to detect accumulating beta amyloid. Once it is seen, they'll begin taking the equivalent of a "statin for the brain" to reduce the load. And Alzheimer's will become as preventable as heart disease is today.
(Source: US News & World Report, By Brian Vastag, Kathryn Roethel, Angela Haupt, Donna Banks, Keith Sinzinger, December 7, 2011)
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