Diagnosis
Insights Give Hope for New Attack on Alzheimer’s
By GINA KOLATA
http://www.nytimes.com/2010/12/14/health/14alzheimers.html?emc=eta1
Alzheimer’s researchers are obsessed with a small, sticky protein fragment, beta amyloid, that clumps into barnaclelike balls in the brains of patients with this degenerative neurological disease.
It is a normal protein. Everyone’s brain makes it. But the problem in Alzheimer’s is that it starts to accumulate into balls — plaques. The first sign the disease is developing — before there are any symptoms — is a buildup of amyloid. And for years, it seemed, the problem in Alzheimer’s was that brain cells were making too much of it.
But now, a surprising new study has found that that view appears to be wrong. It turns out that most people with Alzheimer’s seem to make perfectly normal amounts of amyloid. They just can’t get rid of it. It’s like an overflowing sink caused by a clogged drain instead of a faucet that does not turn off.
That discovery is part of a wave of unexpected findings that are enriching scientists’ views of the genesis of Alzheimer’s disease. In some cases, like the story of amyloid disposal, the work points to new ways to understand and attack the disease. If researchers could find a way to speed up disposal, perhaps they could slow down or halt the disease. Researchers have also found that amyloid, in its normal small amounts, seems to have a purpose in the brain — it may be acting like a circuit breaker to prevent nerve firing from getting out of control. But too much amyloid can shut down nerves, eventually leading to cell death. That means that if amyloid levels were reduced early in the disease, when excess amyloid is stunning nerve cells but has not yet killed them, the damage might be reversed.
Yet another line of research involves the brain’s default network: a system of cells that is always turned on at some level. It includes the hippocampus, the brain’s memory center, but also other areas, and is the brain’s mind-wandering mode — the part that is active when, for instance, you’re driving in your car and you start thinking about what you will make for dinner. That brain system, scientists find, is exactly the network that is attacked by Alzheimer’s, and protecting it in some way might help keep the brain healthier longer.
For example, during nondreaming sleep, the default network is thought to be less active, like a light bulb that has been dimmed. The network also ramps down during intense and focused intellectual activity, which uses different areas of the brain. One emerging theory suggests that if the default network can be rested, amyloid production might be decreased, allowing even an amyloid disposal system that was partly hobbled by Alzheimer’s to do a better job.
The result of all this work is a renewed vigor in the field. After years in which it was not clear how to attack this devastating disease, scientists have almost an embarrassment of riches. The research is in early stages, of course, and there are many questions about which discoveries and insights will lead to prevention or a treatment that works.
But there is a new hopefulness that, at long last, this terrible disease may eventually be conquered, said Richard Mohs, Alzheimer’s group team leader at Eli Lilly.
“We are much closer and quite optimistic that we will be able to do it,” Dr. Mohs said.
A Key Question
When Dr. Randall Bateman first tried to get funds for an effort to answer a sort of chicken-and-egg question about Alzheimer’s, some grant reviewers turned him down, saying they doubted it would work. But they were wrong. He got his answer, although it took much longer than he expected, and his paper describing his results was just published online Thursday by Science.The question came to him in 2003, when he was a neurology resident. One day he was sitting in the hospital cafeteria at Washington University in St. Louis, taking advantage of free soup and rolls. Dr. David M. Holtzman, a neurology professor, joined him, and the two began to talk about the puzzle of Alzheimer’s. Why, Dr. Bateman wondered, did beta amyloid build up in patients’ brains? Were people making too much? Or were they unable to dispose of what they made?
Great question, Dr. Holtzman replied, but what kind of test could you do to answer it?
Dr. Bateman pondered the issue for a year and finally figured out a method. It would not be easy — study subjects would have to sit around for 36 hours with a catheter in their spinal column collecting cerebrospinal fluid. “I said, ‘I think I can probably develop and do this in about six months,’ ” he told Dr. Holtzman.
Dr. Holtzman had his doubts.
“I thought his idea could work conceptually, but for everything to work just right in a human being was a long shot,” he said.
Dr. Bateman’s plan was to put a catheter into a person’s vein and infuse an ingredient, the amino acid leucine, that cells need to make beta amyloid.
The infused leucine would be chemically modified with a form of carbon that did not affect its function or safety but that made it easy to detect newly made amyloid as it was flushed out into the spinal fluid. And since he knew how much leucine he gave people, he could measure how much amyloid they made and then see how fast it was drained.
When the study began, Dr. Bateman was his own first subject. He then did the test on people in their 30s and 40s, as well as healthy older people and people with Alzheimer’s.
He finally completed the study, getting his answer in seven years, rather than the six months he had naïvely expected.
The problem in Alzheimer’s, he found, is disposal. Beta amyloid, he found, normally is disposed of extremely quickly — within eight hours, half the beta amyloid in the brain has been washed away, replaced by new beta amyloid.
With Alzheimer’s disease, Dr. Bateman discovered, beta amyloid is made at a normal rate, but it hangs around, draining at a rate that is 30 percent slower than in healthy people the same age. And healthy older people, in turn, clear the substance from their brains more slowly than healthy younger people.
That means that it might be possible to attack Alzheimer’s not just by getting rid of beta amyloid but also by speeding its disposal. And, he says, there is a clear message in his results.
“What we think may be happening is that a clearance mechanism is broken first,” Dr. Bateman says. Slowly, as years go by, beta amyloid starts to accumulate in the brain. If that clearance can be fixed, or enhanced, the buildup might never occur.
Beta Amyloid as Signal Control
For years, Alzheimer’s researchers wondered if the brain used small molecules of beta amyloid or if those fragments, produced when a larger protein is snipped, were more like scraps of fabric, serving no purpose and just getting in the way.
Now, some say they may have an answer. Beta amyloid, in small quantities, seems to control signaling between nerve cells, reducing the strength of signals when they are too strong. But when it accumulates, the brain can have too much of a good thing. Nerve impulses can be stopped dead, nerves can die, and the disease can take hold, according to this idea.
The work leading to this conclusion began a few years ago when Dr. Roberto Malinow of the University of California, San Diego, decided to look at whether beta amyloid affects synapses, the functional connections between nerve cells. Electrical signals are transmitted through synapses as they travel from nerve cell to nerve cell. And nerve cells make beta amyloid and release it onto their synapses. Was it doing anything there?
One way to find out, Dr. Malinow reasoned, would be to genetically engineer nerves to overproduce beta amyloid and determine what happened to their signaling in laboratory experiments.
The signals, he found, were muffled.
As Dr. Malinow and his colleagues inquired further they discovered that beta amyloid seemed to be part of a nerve cell feedback loop. A nerve will start firing, but under some conditions, the signal can get too intense. Then the nerve releases beta amyloid, bringing the signaling down to normal levels, at which point the nerve stops releasing beta amyloid.
The impact of beta amyloid on synapses was “a very clear effect,” at least in the lab, Dr. Malinow said.
“We proposed that maybe a-beta was normally part of a negative feedback system,” Dr. Malinow said, using a shorthand reference to beta amyloid.
The damage — and Alzheimer’s disease — comes in if there are too many clumps of beta amyloid in the brain. When that happens, the signals between nerve cells are reduced too much, effectively stopping communication.
“Too much of a good thing is bad,” says Dr. Dennis Selkoe, a professor of neurologic diseases at Harvard Medical School. Still, treatment at that point, before the nerves are dying, might reverse the disease.
There may be another way to protect nerves from too much beta amyloid, and it involves a different protein linked to Alzheimer’s. Problems with it show up in the brains of Alzheimer’s patients later, after there has already been a buildup of beta amyloid.
The protein is tau, an integral part of normal cells. It becomes tangled and twisted in Alzheimer’s, after cells are already dying, looking like strands of tangled spaghetti. For decades researchers have argued about whether those distorted tau molecules were a cause or an effect of nerve cell death. Now, they believe they may have an answer, which is spurring the search for drugs to salvage tau and protect the brain from beta amyloid.
New studies by Dr. Lennart Mucke, a neurology professor at the University of California, San Francisco, and director of the Gladstone Institute of Neurological Disease there, and others suggest that tau facilitates beta amyloid’s lethal effects. In genetically engineered mice and in laboratory experiments, the researchers found that without tau, beta amyloid cannot impair nerve cells.
If tau also plays the same role in the brains of humans, that might resolve a longstanding mystery. Occasionally, in autopsies pathologists find that people who had normal memories had lots of plaques in their brains. Perhaps those people, for some reason, made very little tau or were naturally resistant to the injurious interaction between tau and beta amyloid. Could that be why they somehow endured a buildup of beta amyloid?
“That’s a very interesting question,” Dr. Mucke said. “We don’t know the answer.” But, he adds, researchers “should try to learn from such cases how to better fight the disease.”
Early Detection Crucial
In order to treat Alzheimer’s before it is too late, scientists now believe they have to detect it much earlier, before there are symptoms. To do that, they have developed several new methods, including brain scans that can show amyloid plaques in living patients. And for Dr. Marcus E. Raichle, a neurologist at Washington University, what the scans showed was a revelation.
“I was absolutely struck by where this stuff was accumulating in the brain,” he said.
Amyloid was in exactly the areas he was studying, the default network. It is used not only in daydreaming but in memory and in the sense of self. For example, if a man is shown a list of adjectives — honest, kind, thoughtful — and asked if they reflect the way he thinks of himself, the man will use his default network.
“It seems to be a target of Alzheimer’s disease, which I found stunning,” Dr. Raichle said.
The entire default network, and only the default network, was under attack.
The default network is costly for the brain to run, using huge amounts of glucose, Dr. Raichle said. And one indication that a person is getting Alzheimer’s is that in scans, the brain’s glucose use is markedly lower. The observation that Alzheimer’s attacks the default network, then, explains the observation that a low use of glucose by the brain is associated with Alzheimer’s disease.
“The default network has a unique metabolic profile,” Dr. Raichle said. “That opens up a whole set of biological questions about how these synapses are operating.”
“Why does Alzheimer’s attack that region?” he asked. “The simple answer is, we don’t know.”
Meanwhile, Dr. Holtzman was doing a different sort of experiment that turned out to bear directly on what Dr. Raichle was finding.
He found a way to measure amyloid levels in the brains of living mice. He would drill a small hole in each one’s skull and insert a probe that allowed beta amyloid to be collected.
Dr. Holtzman kept the probes in while the animals were eating and running around their cages and when they were sleeping. Beta amyloid synthesis increased when they were awake, when the default network is most active, and decreased when they slept.
His colleagues, Dr. David Brody at Washington University and Dr. Sandra Magnoni of Milan University, then devised an experiment in people. Their subjects were in comas following head trauma or strokes. Often, doctors drill a small hole in these patients’ skulls and insert a catheter to monitor fluids in the brain. Dr. Brody and Dr. Magnoni asked if they could also measure beta amyloid.
They found that the less active the person’s brain, the less beta amyloid it made. That made the researchers ask whether something similar was happening during sleep — the default network was less active, so perhaps less beta amyloid was being made. If so, the implication, which Dr. Holtzman is studying, is that people who are sleep-deprived might be at greater risk of Alzheimer’s.
Another question is whether, as observations have suggested, people with more education are less prone to develop Alzheimer’s disease. Dr. Holtzman’s hypothesis is that education, by encouraging more deliberate problem-solving and thought, decreases the activity of the default network, which is not highly engaged with such focused activity.
At this point, with so many threads of research pointing to so many ideas about Alzheimer’s, everything is a target for treatments to prevent or slow the disease — enhancing the brain’s beta amyloid disposal system, interfering with nerve cells’ feedback loops, blocking tau, protecting the brain’s default network by focusing on its unique metabolic properties.
But researchers say the best hope for the immediate future is with experimental drugs, now being tested, that slow beta amyloid production. The hope is that if the flow of amyloid into the brain is slowed, levels can go down even if the amyloid drain is slightly clogged. The drugs might work even if the problem is with the drain, not the faucet.
The trick in Alzheimer’s, though, might be to start treatment before too much damage is done.
And, said Dr. Samuel E. Gandy, a neurology professor at Mount Sinai School of Medicine, there are some big questions that will have to be answered soon.
“The question for the amyloid folks is, How early is early enough to start treatment? How long is long enough to treat? And what are the other targets we should be attacking?”
But for now, Dr. Holtzman says, the new findings are offering hope.
“We have a richer view of the genesis of Alzheimer’s disease as well as new directions for research, prevention and treatment,” he said.
By GINA KOLATA
http://www.nytimes.com/2010/12/14/health/14alzheimers.html?emc=eta1
Alzheimer’s researchers are obsessed with a small, sticky protein fragment, beta amyloid, that clumps into barnaclelike balls in the brains of patients with this degenerative neurological disease.
It is a normal protein. Everyone’s brain makes it. But the problem in Alzheimer’s is that it starts to accumulate into balls — plaques. The first sign the disease is developing — before there are any symptoms — is a buildup of amyloid. And for years, it seemed, the problem in Alzheimer’s was that brain cells were making too much of it.
But now, a surprising new study has found that that view appears to be wrong. It turns out that most people with Alzheimer’s seem to make perfectly normal amounts of amyloid. They just can’t get rid of it. It’s like an overflowing sink caused by a clogged drain instead of a faucet that does not turn off.
That discovery is part of a wave of unexpected findings that are enriching scientists’ views of the genesis of Alzheimer’s disease. In some cases, like the story of amyloid disposal, the work points to new ways to understand and attack the disease. If researchers could find a way to speed up disposal, perhaps they could slow down or halt the disease. Researchers have also found that amyloid, in its normal small amounts, seems to have a purpose in the brain — it may be acting like a circuit breaker to prevent nerve firing from getting out of control. But too much amyloid can shut down nerves, eventually leading to cell death. That means that if amyloid levels were reduced early in the disease, when excess amyloid is stunning nerve cells but has not yet killed them, the damage might be reversed.
Yet another line of research involves the brain’s default network: a system of cells that is always turned on at some level. It includes the hippocampus, the brain’s memory center, but also other areas, and is the brain’s mind-wandering mode — the part that is active when, for instance, you’re driving in your car and you start thinking about what you will make for dinner. That brain system, scientists find, is exactly the network that is attacked by Alzheimer’s, and protecting it in some way might help keep the brain healthier longer.
For example, during nondreaming sleep, the default network is thought to be less active, like a light bulb that has been dimmed. The network also ramps down during intense and focused intellectual activity, which uses different areas of the brain. One emerging theory suggests that if the default network can be rested, amyloid production might be decreased, allowing even an amyloid disposal system that was partly hobbled by Alzheimer’s to do a better job.
The result of all this work is a renewed vigor in the field. After years in which it was not clear how to attack this devastating disease, scientists have almost an embarrassment of riches. The research is in early stages, of course, and there are many questions about which discoveries and insights will lead to prevention or a treatment that works.
But there is a new hopefulness that, at long last, this terrible disease may eventually be conquered, said Richard Mohs, Alzheimer’s group team leader at Eli Lilly.
“We are much closer and quite optimistic that we will be able to do it,” Dr. Mohs said.
A Key Question
When Dr. Randall Bateman first tried to get funds for an effort to answer a sort of chicken-and-egg question about Alzheimer’s, some grant reviewers turned him down, saying they doubted it would work. But they were wrong. He got his answer, although it took much longer than he expected, and his paper describing his results was just published online Thursday by Science.The question came to him in 2003, when he was a neurology resident. One day he was sitting in the hospital cafeteria at Washington University in St. Louis, taking advantage of free soup and rolls. Dr. David M. Holtzman, a neurology professor, joined him, and the two began to talk about the puzzle of Alzheimer’s. Why, Dr. Bateman wondered, did beta amyloid build up in patients’ brains? Were people making too much? Or were they unable to dispose of what they made?
Great question, Dr. Holtzman replied, but what kind of test could you do to answer it?
Dr. Bateman pondered the issue for a year and finally figured out a method. It would not be easy — study subjects would have to sit around for 36 hours with a catheter in their spinal column collecting cerebrospinal fluid. “I said, ‘I think I can probably develop and do this in about six months,’ ” he told Dr. Holtzman.
Dr. Holtzman had his doubts.
“I thought his idea could work conceptually, but for everything to work just right in a human being was a long shot,” he said.
Dr. Bateman’s plan was to put a catheter into a person’s vein and infuse an ingredient, the amino acid leucine, that cells need to make beta amyloid.
The infused leucine would be chemically modified with a form of carbon that did not affect its function or safety but that made it easy to detect newly made amyloid as it was flushed out into the spinal fluid. And since he knew how much leucine he gave people, he could measure how much amyloid they made and then see how fast it was drained.
When the study began, Dr. Bateman was his own first subject. He then did the test on people in their 30s and 40s, as well as healthy older people and people with Alzheimer’s.
He finally completed the study, getting his answer in seven years, rather than the six months he had naïvely expected.
The problem in Alzheimer’s, he found, is disposal. Beta amyloid, he found, normally is disposed of extremely quickly — within eight hours, half the beta amyloid in the brain has been washed away, replaced by new beta amyloid.
With Alzheimer’s disease, Dr. Bateman discovered, beta amyloid is made at a normal rate, but it hangs around, draining at a rate that is 30 percent slower than in healthy people the same age. And healthy older people, in turn, clear the substance from their brains more slowly than healthy younger people.
That means that it might be possible to attack Alzheimer’s not just by getting rid of beta amyloid but also by speeding its disposal. And, he says, there is a clear message in his results.
“What we think may be happening is that a clearance mechanism is broken first,” Dr. Bateman says. Slowly, as years go by, beta amyloid starts to accumulate in the brain. If that clearance can be fixed, or enhanced, the buildup might never occur.
Beta Amyloid as Signal Control
For years, Alzheimer’s researchers wondered if the brain used small molecules of beta amyloid or if those fragments, produced when a larger protein is snipped, were more like scraps of fabric, serving no purpose and just getting in the way.
Now, some say they may have an answer. Beta amyloid, in small quantities, seems to control signaling between nerve cells, reducing the strength of signals when they are too strong. But when it accumulates, the brain can have too much of a good thing. Nerve impulses can be stopped dead, nerves can die, and the disease can take hold, according to this idea.
The work leading to this conclusion began a few years ago when Dr. Roberto Malinow of the University of California, San Diego, decided to look at whether beta amyloid affects synapses, the functional connections between nerve cells. Electrical signals are transmitted through synapses as they travel from nerve cell to nerve cell. And nerve cells make beta amyloid and release it onto their synapses. Was it doing anything there?
One way to find out, Dr. Malinow reasoned, would be to genetically engineer nerves to overproduce beta amyloid and determine what happened to their signaling in laboratory experiments.
The signals, he found, were muffled.
As Dr. Malinow and his colleagues inquired further they discovered that beta amyloid seemed to be part of a nerve cell feedback loop. A nerve will start firing, but under some conditions, the signal can get too intense. Then the nerve releases beta amyloid, bringing the signaling down to normal levels, at which point the nerve stops releasing beta amyloid.
The impact of beta amyloid on synapses was “a very clear effect,” at least in the lab, Dr. Malinow said.
“We proposed that maybe a-beta was normally part of a negative feedback system,” Dr. Malinow said, using a shorthand reference to beta amyloid.
The damage — and Alzheimer’s disease — comes in if there are too many clumps of beta amyloid in the brain. When that happens, the signals between nerve cells are reduced too much, effectively stopping communication.
“Too much of a good thing is bad,” says Dr. Dennis Selkoe, a professor of neurologic diseases at Harvard Medical School. Still, treatment at that point, before the nerves are dying, might reverse the disease.
There may be another way to protect nerves from too much beta amyloid, and it involves a different protein linked to Alzheimer’s. Problems with it show up in the brains of Alzheimer’s patients later, after there has already been a buildup of beta amyloid.
The protein is tau, an integral part of normal cells. It becomes tangled and twisted in Alzheimer’s, after cells are already dying, looking like strands of tangled spaghetti. For decades researchers have argued about whether those distorted tau molecules were a cause or an effect of nerve cell death. Now, they believe they may have an answer, which is spurring the search for drugs to salvage tau and protect the brain from beta amyloid.
New studies by Dr. Lennart Mucke, a neurology professor at the University of California, San Francisco, and director of the Gladstone Institute of Neurological Disease there, and others suggest that tau facilitates beta amyloid’s lethal effects. In genetically engineered mice and in laboratory experiments, the researchers found that without tau, beta amyloid cannot impair nerve cells.
If tau also plays the same role in the brains of humans, that might resolve a longstanding mystery. Occasionally, in autopsies pathologists find that people who had normal memories had lots of plaques in their brains. Perhaps those people, for some reason, made very little tau or were naturally resistant to the injurious interaction between tau and beta amyloid. Could that be why they somehow endured a buildup of beta amyloid?
“That’s a very interesting question,” Dr. Mucke said. “We don’t know the answer.” But, he adds, researchers “should try to learn from such cases how to better fight the disease.”
Early Detection Crucial
In order to treat Alzheimer’s before it is too late, scientists now believe they have to detect it much earlier, before there are symptoms. To do that, they have developed several new methods, including brain scans that can show amyloid plaques in living patients. And for Dr. Marcus E. Raichle, a neurologist at Washington University, what the scans showed was a revelation.
“I was absolutely struck by where this stuff was accumulating in the brain,” he said.
Amyloid was in exactly the areas he was studying, the default network. It is used not only in daydreaming but in memory and in the sense of self. For example, if a man is shown a list of adjectives — honest, kind, thoughtful — and asked if they reflect the way he thinks of himself, the man will use his default network.
“It seems to be a target of Alzheimer’s disease, which I found stunning,” Dr. Raichle said.
The entire default network, and only the default network, was under attack.
The default network is costly for the brain to run, using huge amounts of glucose, Dr. Raichle said. And one indication that a person is getting Alzheimer’s is that in scans, the brain’s glucose use is markedly lower. The observation that Alzheimer’s attacks the default network, then, explains the observation that a low use of glucose by the brain is associated with Alzheimer’s disease.
“The default network has a unique metabolic profile,” Dr. Raichle said. “That opens up a whole set of biological questions about how these synapses are operating.”
“Why does Alzheimer’s attack that region?” he asked. “The simple answer is, we don’t know.”
Meanwhile, Dr. Holtzman was doing a different sort of experiment that turned out to bear directly on what Dr. Raichle was finding.
He found a way to measure amyloid levels in the brains of living mice. He would drill a small hole in each one’s skull and insert a probe that allowed beta amyloid to be collected.
Dr. Holtzman kept the probes in while the animals were eating and running around their cages and when they were sleeping. Beta amyloid synthesis increased when they were awake, when the default network is most active, and decreased when they slept.
His colleagues, Dr. David Brody at Washington University and Dr. Sandra Magnoni of Milan University, then devised an experiment in people. Their subjects were in comas following head trauma or strokes. Often, doctors drill a small hole in these patients’ skulls and insert a catheter to monitor fluids in the brain. Dr. Brody and Dr. Magnoni asked if they could also measure beta amyloid.
They found that the less active the person’s brain, the less beta amyloid it made. That made the researchers ask whether something similar was happening during sleep — the default network was less active, so perhaps less beta amyloid was being made. If so, the implication, which Dr. Holtzman is studying, is that people who are sleep-deprived might be at greater risk of Alzheimer’s.
Another question is whether, as observations have suggested, people with more education are less prone to develop Alzheimer’s disease. Dr. Holtzman’s hypothesis is that education, by encouraging more deliberate problem-solving and thought, decreases the activity of the default network, which is not highly engaged with such focused activity.
At this point, with so many threads of research pointing to so many ideas about Alzheimer’s, everything is a target for treatments to prevent or slow the disease — enhancing the brain’s beta amyloid disposal system, interfering with nerve cells’ feedback loops, blocking tau, protecting the brain’s default network by focusing on its unique metabolic properties.
But researchers say the best hope for the immediate future is with experimental drugs, now being tested, that slow beta amyloid production. The hope is that if the flow of amyloid into the brain is slowed, levels can go down even if the amyloid drain is slightly clogged. The drugs might work even if the problem is with the drain, not the faucet.
The trick in Alzheimer’s, though, might be to start treatment before too much damage is done.
And, said Dr. Samuel E. Gandy, a neurology professor at Mount Sinai School of Medicine, there are some big questions that will have to be answered soon.
“The question for the amyloid folks is, How early is early enough to start treatment? How long is long enough to treat? And what are the other targets we should be attacking?”
But for now, Dr. Holtzman says, the new findings are offering hope.
“We have a richer view of the genesis of Alzheimer’s disease as well as new directions for research, prevention and treatment,” he said.