Originally created 08/20/00

Search for cause progresses

The links between Alzheimer's disease and other afflictions such as heart disease might hold the key to unlocking how the disease kills brain cells and steals memories and lives, a local researcher said.

America stands at the beginning of an epidemic in Alzheimer's disease, with aging baby boomers expected to swell the number afflicted from 4 million to 14 million in the next 50 years, according to the Alzheimer's Association.

But Alzheimer's research also appears poised to see some significant breakthroughs in the coming years, as scientists zero in on potential causes. Cautious optimism is following the announcement of preliminary research on a vaccinethat, in mice, eliminated the telltale sticky brain tangles known as beta amyloid plaques, which are a hallmark of the disease.

"That's what's exciting because it suggests that in individuals who have already developed AD, that there's a potential for removing some of the plaques," said William David Hill, an Alzheimer's researcher at Medical College of Georgia, co-director of the Brain Bank Unit and director of the MCG Primate Brain Bank. "That would be the first step toward reversing some of the symptoms of the disease."

It might also help settle a longstanding question among researchers, Dr. Hill said: Are the plaques a cause of brain neuron death or a symptom of an underlying process that creates them?

Plaques created by the soluble form of the naturally occurring beta amyloid peptide might just indicate there is a lot of it around, and it is that free-floating beta amyloid that is the real culprit, Dr. Hill said. Of the three hot areas of Alzheimer's research now, certainly one is the vaccine, which uses a synthetic form of the beta amyloid protein to rally an immune response.

But another area is looking at whether there is an immune response gone awry with Alzheimer's that may be causing the damage to brain cells. Dr. Hill also is looking at whether there are potential interactions between the beta amyloid protein and other proteins and genes implicated in other problems.

It is known that having the genetic trait known as the "apoE4" - or apolipoprotein - allele puts one at higher risk for Alzheimer's and cardiovascular disease, Dr. Hill said. Apolipoprotein is involved in transporting cholesterol and might be altering lipids on cell membranes to allow beta amyloid easier access, Dr. Hill said.

In last week's New England Journal of Medicine, researchers using functional MRI scans of people with apoE4 with normal memory found that their brains had greater activation than those without the trait, suggesting the brains had to use greater resources to perform the memory tests. The greater degree of brain activation also correlated with memory decline on follow-up tests two years later.

Beta amyloid also binds with a receptor on the cell surface for advanced glycation endproducts (AGE), which are a form of oxidative damage also found in the plaques and which also might be implicated in the destruction of brain cells that accompanies Alzheimer's, Dr. Hill said.

Dr. Jerry Buccafusco, director of the Alzheimer's Research Center at Medical College of Georgia and a research pharmacologist at the Department of Veterans Affairs Medical Centers, is studying AGE and its potential role in Alzheimer's. AGE appears to be involved in cardiovascular disease and the stiffening of arteries associated with diabetes, Dr. Buccafusco said.

There might be another culprit at work. Using genetic material from human brains, Dr. Hill was able to isolate a blood-borne protein that seems to interact with beta amyloid and might help explain why the naturally occurring protein turns into a wrecking ball.

"This may be a link between the oxidative damage and the development of the disease," Dr. Hill said. "We think we're seeing this protein at higher levels in people with Alzheimer's disease. There is a polymorphism (genetic trait) in the gene that helps regulate this protein and that also looks like it's at higher levels (in people with Alzheimer's). This is all preliminary data, and we're trying to confirm it in larger groups of patients."

Some researchers also are testing compounds that seek to limit the amount of presenilin, a protein enzyme that appears essential in forming the toxic beta amyloid peptide, thereby limiting its prevalence, Dr. Hill said.

Like many diseases, Alzheimer's disease takes multiple forms and thus could have multiple causes, Dr. Hill said. Currently, the only two drugs approved to treat it - Aricept and Cognex - don't stop the disease process and only temporarily improve thinking in some people by raising the amount of the acetylcholine available.

But the new approaches seem to be inching closer to finding the disease's roots and pointing the way to stopping it.

"I don't want to get anyone's hopes up too much," Dr. Hill said, "but I think there is more reason now to hope than in previous years.


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