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Probing the mind for a cure

A neuroscientist discusses Alzheimer's and where the research is going next.

Published September 16, 2003

About 4-million Americans have Alzheimer's, a progressive disease that damages and destroys brain cells.

Dr. Samuel Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and vice chairman of the National Medical and Scientific Advisory Council of the Alzheimer's Association, says researchers are narrowing their lists of suspected causes and potential treatments for the devastating illness.

Gandy spoke in a conference call last week as part of the American Medical Association's annual Science Reporters Conference in Philadelphia. Here are excerpts:

On what Alzheimer's is:

It is a dementia, a loss of the ability to meditate or think. About half of the over-85 population suffers from dementia of some sort, and about three-quarters of that is due to Alzheimer's.

Do we know it when we see it?

There are typical clinical, biochemical and pathological features used to define the disease. It is still only possible to definitely determine (through) a brain biopsy or in an autopsy after death. (Symptoms are) loss of the ability to form new memory, trouble with short-term memory, disturbances of emotion, and psychosis.

Changes in the brain:

Alzheimer's is typically associated with declining levels of a neurotransmitter in the cortex of the brain. We believe it begins with amyloid buildup: a gooey, sticky material that forms clumps throughout the cortex. Amyloid is produced by cells and floats around in bodily fluids throughout life. This normally soluble peptide, after five or six decades, is somehow motivated to change its shape and expose a sticky part of its structure. These deposits build up only in the brain.

Deciding on the best target:

We've compared amyloid to cholesterol. The fat of cholesterol accumulates in blood vessels. In Alzheimer's, there's buildup of peptide in the brain. They're (both) called plaque, but they are made of distinctive material. What we're beginning to see are strategies to retard amyloid formation or increase the ability of the brain to destroy amyloids. That will tell us if amyloids are responsible for all Alzheimer's disease.

Promising avenues:

Recent studies are on medicines used to control cholesterol, the statins class. For reasons we don't yet understand, statins activate the good pathways and cause amyloid to be broken down. In one study, (the statin drug) Lipitor lowered amyloid formation.

In need of a biomarker:

One of the chief challenges is ... to identify who is beginning to develop the disease. One method is to look (for) a blood or spinal fluid test that could be used as a marker for amyloid levels in the brain. One challenge in the pharmaceutical industry is there is no reliable way to follow the impact of anti-amyloid drugs. (Gandy and others are studying chemical markers that reflect amyloid levels.) Then we could be looking for levels of amyloids even in teenagers.

Anti-inflammatory drugs were showing promise, but . . .

It was noted years ago that people with arthritis taking nonsteroidals seemed to have a decreased risk of developing Alzheimer's. A large clinical trial ultimately turned out negative. But there is new evidence that a subgroup (of that type of drug) could actually work as enzyme modulators. Ibuprofen is one.

Mouse as man's best friend:

In a mouse model of Alzheimer's we looked at the variables that include aging, gender, genetic factors. (University of South Florida researchers have found that genes used to make memories shut down in mice with Alzheimer's.) We were able to show that the pattern of amyloid levels, particularly in male mice, rose (with human gene presence) for Alzheimer's. A vaccine with synthetic amyloid peptides was tested in rodents and was very effective.

How about humans?

(In another phase), 360 people were vaccinated and 15 developed an allergic encephalitis, or severe inflammation of the brain. Of those 15, 14 recovered. One was left with permanent deficit. So injection into people at risk for Alzheimer's is not receiving a lot of enthusiasm these days. Instead, antibodies to the amyloid (might) be made in a test tube, then introduced periodically in the bloodstream, sort of like chemotherapy for cancer.

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