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.

David Bennett of the Rush Alzheimer's Disease Center in Chicago persuaded more than 2,000 older people who had no signs of dementia to undergo cognitive testing, beginning in 1992. As they aged, some of the people developed cognitive difficulties. Some had mild cognitive symptoms. Some none. Some developed full-bore Alzheimer's.

The participants agreed that after death their brains would be available for autopsy. Bennett has examined 660 of the brains. Only about a third of the people had developed symptoms of dementia. Yet Bennett found that more than 90% of the brains bore the plaque/tangle hallmarks of the disease. Some people who had the symptoms did not have the tau tangles or the beta amyloid plaques. Some who didn't have the symptoms had the plaques or tangles; some had both.

The implications of this are confounding and frightening. Could it be that Alzheimer's is not a specific disease, but a normal part of growing old?

Bennett recoils at the implication. Alzheimer's might be associated with aging; that doesn't mean it is caused by it, he said. "Alzheimer's disease is extremely common. The estimates are probably gross underestimates. Is it statistically normal? Yes. But if you use normal to mean the same as puberty, something inevitable, no, absolutely not."

He notes that ancient Egyptians all developed tooth decay by age 40. "But there was nothing normal about it -- it was the environment," he said.

Marcelle Morrison-Bogorad, associate director of the National Institute on Aging's neuroscience and neuropsychology of aging program, finds Bennett's data deeply disturbing.

She said "the distinction is getting fuzzier and fuzzier between normal aging and diseases like Alzheimer's disease. This brings into question if these people are normal or not. I don't think we can tell anymore who is normal.

"It worries me a lot, actually, because we've been trying to reassure people who are older that small lapses in memory are part of normal aging. . . . This research is suggesting, not proving, that it might be a sign of something down the road. That's not good news."