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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

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."

To say that Alzheimer's is normal is not something anyone wants to hear. Medicine can't stop people from getting old. And you can't fix old age. Other than the simple arithmetic of it, no one really even knows what aging is. They know what accompanies it; they haven't a clue what causes it.

Some people, of course, live to be 100 and never suffer dementia. But dementia is clearly associated with old age. Any individual's probability of having Alzheimer's is the sum total of a variety of factors.

Gary Lynch of UC Irvine summarized those factors as a combination of an individual's genetic endowment, pre-birth conditions, life experiences, environmental conditions and health accidents. If, for example, you were born with a mutation of a particular lipid transport gene and you had banged your head on the pavement when you were 12, your chances of having Alzheimer's would be many times greater than someone who had the right genes and wore a helmet religiously when skateboarding.

Pharma difficulties

Eric Karran, chief scientific officer at pharmaceutical giant Eli Lilly & Co., states the obvious when he says his industry is "in a lot of trouble at the moment." New drug candidates are failing trials. Old drugs are the subjects of lawsuits. The industry is accused of having insufficient concerns about the safety of its products while being urged by specific patient groups to take more risks to develop medicines for them. Patents are expiring on successful drugs, meaning revenue for many companies is about to fall off what is darkly referred to within the industry as the patent cliff.

The failure to learn what causes Alzheimer's has made development of ways to treat it problematic, but the pharmaceutical industry has already sunk billions into Alzheimer's programs. The disease is too tempting a financial target to ignore.

Much of the basic research of the last decade has been aimed at building an understanding of how the normal process within brain cells can break down. That process is an elaborate one, involving what biologists call cascades of events -- dozens, to perhaps hundreds, of steps long. Every step represents a point of potential failure. Each also represents a point of potential intervention. Science has learned to intervene in many normal biological processes by manufacturing molecules that will disrupt one step, thus halting the cascade. That's the theory, but it is also the biggest obstacle. The cascade wouldn't exist if it didn't do something useful.

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