Fighting Alzheimer's Disease: Go for the Beta-Amyloid!

From the WebMD Archives

Nov. 6, 2000 -- In the war against Alzheimer's disease, researchers are stocking the arsenal with a barrage of different weapons, both drugs and vaccines, aimed at a single target -- the deadly protein beta-amyloid.

"We need multiple strategies working against beta-amyloid buildup," Rachel S. Doody, MD, PhD, tells WebMD. "It's important to realize that these treatments are still under development and are far from ready for use in patients." Doody is the Effie Marie Cain professor in Alzheimer's disease research at Baylor College of Medicine in Houston.

Beta-amyloid protein accumulates in the brains of patients with Alzheimer's disease, activating immune cells that try unsuccessfully to remove it. That triggers the release of poisons that ultimately kill nerve cells, leaving behind a trail of plaques and tangles -- the remains of nerve cells and fibers, clogged up with beta-amyloid.

As Alzheimer's is the most common cause of dementia, or progressive memory loss and thinking problems, in the elderly, and has no effective treatment, it is a formidable opponent. It affects more than 4 million Americans, and without a cure or effective prevention, that number may swell to 14 million in 50 years.

This week, researchers are gathering in New Orleans at the Society for Neuroscience's 30th Annual Meeting, where details of the latest battle plans, mostly being conducted on animals, will be unveiled. "Going from animals to humans will take some time," Juan Troncoso, MD, an associate professor of pathology and neurology at Johns Hopkins University in Baltimore, tells WebMD. "The animal model is not a perfect replica of Alzheimer's disease."

There are a number of strategies being developed by those on the front line of research. The first: Decrease beta-amyloid production. Researchers at Elan Pharmaceuticals in South San Francisco and Eli Lilly and Co. in Indianapolis have found a new class of drugs that decrease beta-amyloid production by blocking gamma-secretase, an enzyme that separates beta-amyloid from a larger protein and releases it into the brain.

"Gamma-secretase is a critical target for treatment of Alzheimer's disease, as beta-amyloid is the core building block of the plaque," Dale B. Schenk, PhD, vice president of discovery research at Elan, tells WebMD. "This work is a stepping stone toward treatments that will eventually enter the clinic."

"As gamma-secretase blockers decrease beta-amyloid both in cell and animal models of Alzheimer's disease, there is reason to hope that they would do the same in humans," Doody says.

The primary goal of gamma-secretase inhibitors is to treat patients who already have Alzheimer's, in whom these drugs should prevent further beta-amyloid buildup. "The brain has some capacity to clear plaques," Schenk says. "The hope is that the [plaques] will slowly clear up over time."

Another strategy is to prevent beta-amyloid buildup and the toxic damage it causes. Metals in the brain, such as copper and zinc, bind to beta-amyloid, causing it to accumulate in Alzheimer's and trigger reactions that release toxic byproducts, which can create more damage. Researchers at Harvard University in Boston used drugs called chelators to trap copper and zinc, and tested them in an animal model.

When mice were given copper and zinc chelators by mouth for 12 weeks, beta-amyloid accumulation decreased so dramatically that some treated animals had none left.

"These mice did extremely well -- their general health and performance on a behavioral rating scale were actually much better than in untreated animals," Ashley I. Bush, MD, PhD, tells WebMD. He is an associate professor of psychiatry at Harvard and director of the Laboratory for Oxidation Biology at Massachusetts General Hospital.

"This very exciting development is effective in mice; we hope it will work as well in humans, and it will take us about a year to find out," Colin L. Masters, MD, a professor of pathology at the University of Melbourne in Parkville, Australia, tells WebMD.

Masters has started some early clinical testing of these drugs in humans, with no apparent adverse effects to date. Four years may elapse before these drugs are clinically available. These types of medications may have broader application to other diseases of aging, including Parkinson's disease, cataracts, and Lou Gehrig's disease.

Doody hopes that publicity surrounding this research will not encourage patients to seek chelation therapies offered in some nutritional or alternative clinics, as commercially available chelators have not been tested in Alzheimer's disease or other diseases of aging, and may have unwanted side effects.

A third line of attack to fight Alzheimer's is to use beta-amyloid itself to enlist the body's immune defenses to turn on the protein with full force and blast it out of the brain.

When mice were vaccinated with beta-amyloid from humans, they developed antibodies to the protein, suggesting that their immune systems had launched an attack against it, and the amount of beta-amyloid in the brain was significantly less in the vaccinated mice than in untreated mice.

"The vaccine may stimulate cells to remove beta-amyloid from the brain, but to be effective, it has to be done as soon as possible," Troncoso tells WebMD.

In late stages of Alzheimer's disease, there is so much damage to both nerve cells and their connections that removing beta-amyloid would be futile, explains the Hopkins' researcher. "There's no sense in trying the vaccine in someone who's been in a nursing home for 10 years."

It might be most helpful in patients with early signs of Alzheimer's, or in people at high risk because of a strong family history or genetic tendencies, Doody explains.

"This may be a way to treat Alzheimer's disease, taking due safety precautions," Troncoso says. Side effects in humans could range from "none to very significant," as the immune response might not be restricted to brain amyloid, but also could trigger an autoimmune attack on the kidneys, joints, and other organs. Elan Pharmaceuticals already is doing early safety studies in humans, but FDA approval is probably at least two to five years away.

Schenk holds stock options in Elan Corp., the parent company of Elan Pharmaceuticals. Bush is a consultant and scientific adviser to Prana Biotechnology, Ltd., which sponsored his research at Mass General until September 1999, and is now funding clinical trials by Masters at the University of Melbourne. Bush is a minor shareholder in Prana.