New Ideas Energize Alzheimer's Battle

  By GINA KOLATA  

NY Times, January 14, 2003

Dave Gatley for The New York Times

Dr. Eliezer Masliah's finding that Alzheimer's was a disease of damaged synapse connections has led to possible treatment strategies.

  The clinical signs of Alzheimer's disease are all too familiar — the erosion of memory for recent, then distant events, the declining ability to reason or to think.

Eventually, there is the blank look, a sort of Alzheimer's stare, and a failure to recognize a husband, a wife, a child. But the real question has been, What is going on in the brain, and why do patients suffer the terrible forgetfulness?

For years, the prevailing notion was that Alzheimer's was a disease of brain-cell death. Pathologists could see that progressively, relentlessly, brain cells died, leaving behind piles of debris that they detected in autopsies and that are the hallmarks of the disease.

But now, many researchers are asking if that old hypothesis is correct. They cite accumulating evidence that memory starts to fail long before brain cells die, and that the disease, with its memory loss, begins as an interruption of the signaling between living and healthy brain cells.

If they are right, it may be possible to stop Alzheimer's, and reverse the memory loss, if treatments begin before brain cells die.

The new idea is that the disease starts when small clumps of a protein, amyloid, start interrupting signals between nerve cells in the brain. The synapses, where one cell signals another in the brain's intricate circuitry, no longer function.

Yet, at this early stage of the disease, researchers say, the nerve cells are still alive and well, and the disease might be halted if the clumps of amyloid could be removed or inactivated. But if the disease continues, brain cells start to die. Dead and dying cells accumulate in heaps in the brain, and the injured brain cannot be made whole.

The work is still in a research stage, and the possible therapies are years away, if they pan out at all. But Alzheimer's investigators say they are invigorated because they have some tantalizing ideas of ways to stop the small clusters of amyloid from inflicting injury, giving them hope that they may be able to squelch the disease.

"The nice thing about synapses is that they are very plastic," said Dr. Lennart Mucke of the Gladstone Institute of Neurological Disease and the University of California at San Francisco. "As long as the cell body is intact, nerve cells have a remarkable ability to rebuild their synapses. It is much harder and often impossible to replace whole nerve cells. But if we could interfere with synaptic damage early on, there is a very good chance that cognitive function would come back."

Peter DaSilva for The New York Times

Dr. Lennart Mucke and his colleagues at the Gladstone Institute are studying a protein that may help protect the brain from dementia.

In a sense, researchers say, the evidence has been staring at them for years. It began with a puzzle about the defining feature of Alzheimer's, amyloid plaques, those microscopic patches of debris found in the brain. The plaques, made up of large aggregates of amyloid protein, are unmistakable, pathologists say. They look like tiny stars, about a tenth the thickness of a hair and about five to six times as large as a brain cell.

"One of the main diagnostic features is the deposit of this insoluble material in the brain," said Dr. Eliezer Masliah, a professor of neurosciences and pathology at the University of California at San Diego. "This gunk accumulates in the brain in very specific regions where memory and functions like them happen, like in the frontal cortex and the hippocampus where memories are recorded."

For years, he added, people thought this material was the main problem in Alzheimer's.

But, in 1989, he and Dr. Robert Terry, who was chief of the laboratory there, noticed a problem with the plaque hypothesis. They had brains from people who had been severely demented and those with only mild memory impairment.

They expected to see many more plaques in those with severe dementia. They did not. In fact, they found no tight link between plaque levels and the degree of dementia. "We were quite surprised," Dr. Masliah said. The idea that plaque caused dementia "had been such a dominating force for so many years."

Dr. Masliah proposed another hypothesis. "I thought probably something was going wrong at the level of the connections between the brain cells," he said, reasoning that if the system was not working properly, it might be because the communications between the nerve cells were failing. Those connections, the synapses, which link the cells in complex networks, might be damaged.

But his work was not widely accepted at the time. Why, colleagues asked, were the synapses failing? Was there a link between synaptic damage and dementia? Did it explain the lack of correlation between plaques and the degree of dementia?

In the next decade, other scientists began finding small molecules that, they proposed, might be the culprits in damaging nerve cells. The molecules seemed to be clumps of amyloid protein, Dr. Mucke said, and a new picture was emerging. These small amyloid clumps, he said, "do not just exist in these garbage piles, the plaques, but they also float around like cruise missiles." When they do, they might injure synapses.

Different investigators, stumbling upon various stages of the small clumps independently, gave them different names. They say they struggled for years to persuade colleagues to pay attention.

Dr. William L. Klein, a professor of neurobiology and physiology in the Alzheimer's Disease Core Center at Northwestern University, called them A.D.D.L.'s, for amyloid derived diffusible ligands, and reported that they blocked communication between nerve cells. But, he said, when he first presented his data at a meeting in 1998, the audience of scientists was skeptical. "I overheard some folks saying, `How could that be? Why didn't we see it?' "

In the meantime, Dr. Dennis J. Selkoe of Harvard was finding essentially the same thing — chains of molecules, which he called protofibrils, that disrupted nerve cell communication. The chains consisted of about 100 molecules of amyloid beta protein, compared with thousands in that make up plaque in a fibril.

Dr. Selkoe added the small clumps of molecules to nerve cells in the laboratory. "They killed them," he said, but the cells died more slowly than they did when they were mixed with larger clumps that make plaques. Then, Dr. Selkoe said, he injected protofibrils into rats and found that they interfered with the first steps of memory and learning.

In the meantime, Dr. Mucke studied mice that he and his colleagues genetically modified so that they produced human amyloid proteins. Long before those proteins were deposited in plaques in the animals' brains, he found, nerve synapses were damaged. As a consequence, nerve signals were not being transmitted.

Dr. Masliah, his colleagues and Dr. John Morris, a neurologist at Washington University in St. Louis, looked in the brains of people who had what might have been the earliest stage of Alzheimer's, known as mild cognitive impairment; those who had end stage dementia; and those of older people who were not demented.

When Dr. Masliah examined the brains of people free of dementia, he found healthy synapses. Brains of people with mild impairment had damaged synapses, and the damage was even more pronounced in people with Alzheimer's. That, he said, "suggests to me that Alzheimer's disease is a disease of synaptic connections."

It also suggested a treatment strategy.

"If we believe that the actual plaques are the cause of Alzheimer's disease, then we need to dissolve them and clear them from the brain," Dr. Masliah said.

"But if we believe it is the precursor fragments, then we need to prevent those fragments from being formed," he added. "The plaques are these huge aggregates of smaller components. Imagine that we have a drug that would break the plaque apart. Then you'd have all the little tiny components floating all over the place and the situation would be worse. So we should leave the plaques alone."

Several strategies might work, Dr. Mucke said. All involve interfering with amyloid with the hope that treatment can be started, and the toxic protein blocked, before it starts aggregating in large clusters, forming plaques, and before brain cells die.

One possibility is to stop the production of amyloid with drugs, now under development, that are akin to the protease inhibitors used to treat H.I.V.

Another is to use the body's own immune system, stimulating the production of antibodies that will attach themselves to the small amyloid clusters and sweep them away. "You trigger the immune system into doing a cleanup job," Dr. Mucke said. That is a strategy that works well in mice, but initial studies in humans were halted because some of the patients developed brain inflammations.

"This was not entirely unexpected," Dr. Mucke remarked. "Harnessing the immune system is a tricky business and we have to learn how to fine-tune it."

It also may be possible to enhance the body's own ways of removing the small clusters of amyloid. There are enzymes, like one known as neprilysin, that appear to chew up amyloid, Dr. Mucke said. "People make them normally," he added, explaining that if their levels were increased, it might tip the balance in people developing Alzheimer's, preventing them from accumulating enough of the protein to damage their synapses.

Yet another idea is to try to help the brain cope with the small amyloid proteins. The notion comes from studies linking a cholesterol-carrying protein to a risk of developing Alzheimer's. People can inherit any of three forms of the protein — Apo E2, Apo E3 or Apo E4. Those who have the Apo E4 form are more likely to develop Alzheimer's than those with the other forms of the protein. Dr. Mucke and his colleagues have found that Apo E3 can protect the brains of mice from amyloid. (They have not yet examined Apo E2, which confers an even lower risk than Apo E3.) "If we look at middle-aged mice that make human amyloid and Apo E3, they are fine," Dr. Mucke said. "At the same time, those that make human amyloid and Apo E4 have lost a significant number of synapses."

His colleagues at the Gladstone Institute are developing drugs that convert Apo E4 to apo E3. The two forms of the protein differ in just one amino acid, No. 112 of the chain of 229 amino acids that make it up, and that one amino acid determines how the protein is folded.

They, along with investigators at the University of California at San Francisco, used computer modeling to screen large databases of chemicals for ones that might fit into a groove in the Apo E4 protein and modify its shape so it looks like Apo E3. They found several that looked promising.

"We are still at the cell culture level with these studies," Dr. Mucke said. "But it would be one way of taking advantage of what nature already has in place. We know that this protein has a big impact on Alzheimer's disease. The idea is to take advantage of what nature is revealing to us."

But would it work? Is there any hope that people can regain their memories after the disease process has started?

The task ahead is not likely to be easy, Dr. Mucke and others caution.

"We need to look at Alzheimer's disease as a disease that is as powerful and ferocious as cancer," Dr. Mucke said. "We need to fight it with equally heroic measures." But now, he said, "It is beginning to look like a tractable problem."