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Scientists can't get their minds around Alzheimer's

They still aren't sure what causes the disease or how to cure it. And the stakes have never been higher.

December 27, 2007|By Terry McDermott | Los Angeles Times Staff Writer

By 2010, Alzheimer's care will cost Medicare about $160 billion a year. By 2035, it could overtake the defense budget. One analysis has estimated that by 2050, Alzheimer's will cost Medicare more than $1 trillion annually. Those numbers do not include privately insured and uninsured costs.

"From a social and economic view, it is about the money, the growing diversion of resources to sustain life in those increasingly unaware of their own lives," Harry Tracy wrote recently in NeuroInvestment, his industry newsletter. "There is no greater public health issue looming in the developed world."

While the cost of Alzheimer's soars, federal money spent on research has flattened and is expected to decline in real terms in the future as the competition for federal money heightens. The rising costs of treating the disease coupled with reduced research funding is, to some, a foreboding combination.

Andy Grove, the former chairman of Intel Corp., spoke at this year's Society for Neuroscience convention in San Diego. Grove, who has Parkinson's disease, lamented the lack of a full-scale attack on neurodegenerative disorders: "We are about to experience an explosion of Alzheimer's disease cases. . . . This situation is best compared to astronomers following a meteor hurdling toward San Diego, aimed to hit a very precisely calculated place and time. What would we do if we had such a situation? I think we would take it a little more seriously than we take the economic meteor that's coming just as predictably our way."

Research confusion

It's been 101 years since Alzheimer's disease was first theorized, and 30 years since the federal government began funding research on it, spending, to date, more than $8 billion. Private industry has spent billions more. What has been learned?

The answer is perplexing. There have been more than 35,000 scientific papers published on Alzheimer's just in the last decade. They include hundreds of impressively detailed descriptions of purported disease mechanisms. But in all that wealth of information, there are some rather obvious gaps.

For example, the leading hypothesis of the cause of Alzheimer's, called the amyloid hypothesis, is centered on the overproduction, or inadequate clearance, in the brain of a protein called beta amyloid. Fragments of the protein aggregate into clumps called plaques. These plaques were first observed more than a century ago by the man after whom the disease is named, Alois Alzheimer.

For most of the century since, scientists have believed the plaques were associated with the disease. But to date, they don't know whether amyloid plaques are the cause of the disease or a result. They don't know whether they are vital to the progress of the disease or incidental. They don't even know whether their presence is indicative of the disease.

A rival idea, called the tau hypothesis, is no more definitive. Where beta amyloid generally aggregates outside brain cells, the protein tau aggregates into fibrous structures, called tangles, inside the cells.

The processes by which either amyloid or tau cause brain cells to malfunction, and in some cases die, are neither well understood nor completely coincident with observations of the disease itself.

For a long while, the Alzheimer's field was divided between the two warring camps -- the so-called (beta amyloid) Baptists and Tauists. Now, the two-front war has exploded. The lack of resolution has produced a surfeit of competing hypotheses, the most prominent of which focuses on what happens with beta amyloid before plaques form.

Beta amyloid is common in the brain and not harmful when it exists in single strands. Plaques contain thousands of strands. This new hypothesis holds that much smaller accumulations of the proteins, containing as few as half a dozen strands, are the real culprit in Alzheimer's. These smaller accumulations, called oligomers, are, because of their small size, able to travel between neurons in a way that plaques cannot.

Researchers have discovered that oligomers can be toxic to brain cells long before plaques ever form. This would explain why some people who have been diagnosed with Alzheimer's were not found to have plaques. The evidence that oligomers are dangerous has been so persuasive that many of the leading proponents of the amyloid hypothesis have incorporated them into their models.

Inconveniently for scientists, there are no definitive physical markers for Alzheimer's in living patients. There is no blood test or tissue sample that can be taken and examined. It is diagnosed by the symptoms a patient exhibits, and there is no way to know definitively what is going on inside a patient's brain.

Complicating matters are preliminary results from the first long-term studies.

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