Studies Show New Avenues For Diagnosis and Treatment of Alzheimer's Disease

Alzheimer's Association
Monday, 29 June 1998

Three newly published research papers further clarify the role of an abnormal protein in Alzheimer's disease, and show possible new avenues for diagnosis and treatment of the progressively debilitating brain disease, according to the Alzheimer's Association.

The three studies, which appear in the July 1998 issue of Nature Medicine, all are concerned with an abnormal protein known as beta amyloid. The formation of beta amyloid-protein deposits in the brain, known as plaques, is an established attribute of Alzheimer's disease. Amyloid plaques and neurofibrillary tangles are the two characteristic lesions found in the brains of people with Alzheimer's disease. A question remains about whether the amyloid deposits cause brain cell death in Alzheimer's or are a result of it. The precise role of beta amyloid-protein in Alzheimer's remains unknown.

"What we're seeing emerge in these studies is a clearer picture of what may be the cascade of events that leads to brain cell dysfunction and death in Alzheimer's disease," said Zaven Khachaturian, Ph.D., director of the Association's Ronald & Nancy Reagan Research Institute. "This is very exciting because the more we know about how Alzheimer's disease works, the more opportunities we have to find ways to treat and prevent it."

Primate model for Alzheimer's disease

In "Aging renders the brain vulnerable to beta amyloid-protein toxicity," Changiz Geula, Ph.D., of Beth Israel Deaconess Medical Center, Boston, and Bruce Yankner, M.D., Ph.D., of Children's Hospital, Boston, and colleagues used a newly developed primate model of Alzheimer's disease to strongly suggest that the brain cell death caused by amyloid beta-protein is specific to certain species and related to changes in the aging brain.

Aged rhesus monkeys injected with beta amyloid-protein experienced brain cell death, while no significant cell death occurred in young rhesus monkeys. In addition, the researchers showed that brain cell toxicity was greater in aged rhesus monkeys than in aged marmosets, and was not significant in aged rats.

This is the first time beta amyloid induced brain cell death, at levels similar to that found in Alzheimer's disease, has been produced in an animal model. Scientists still need to determine what happens in the aging brain that makes it vulnerable to beta amyloid-protein. The researchers hypothesize that the connection between aging and brain cell death due to beta amyloid, combined with the relatively long life of humans, may explain our unique susceptibility to Alzheimer's. The researchers also claim the new study helps explain why previous experiments produced mice that had beta amyloid plaques, but no neuron loss.

Possible new blueprint for drug therapies

Because it has been suspected, though not proven, that beta amyloid causes brain cell death in Alzheimer's disease, inhibition of the formation of beta amyloid and plaques is considered a good target for Alzheimer therapies.

In "Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer's therapy," Claudio Soto, Ph.D., of the New York University Medical Center, and colleagues give details of a substance that reduced formation of beta amyloid plaques in rats, and also inhibited an earlier stage event whereby normal amyloid protein transforms into fibers that form into plaques. The substance, a peptide known as iAb 5, also dissolved existing fibers and blocked brain cell death caused by beta amyloid in test tube experiments.

"It is encouraging to see that it is possible to block the formation of plaques," Khachaturian said. "If science shows us that amyloid is, in fact, a causal factor in Alzheimer's, this may prove to be a potent treatment method. Much more research is needed, but this is a promising start."

Next steps might include testing in more complex systems, such as aged primate brains. Questions remain about how well the new substance will cross the blood-brain barrier.

Possible diagnostic tool

There is no single diagnostic test for Alzheimer's disease. Current clinical methods combine physical and neuropsychological testing with caregiver input and the physician's judgment.

Studies show this method to be about 80 to 90% accurate in diagnosing Alzheimer's disease. Genetic information may be useful in people showing symptoms of the disease. Autopsy evidence is used to confirm clinical diagnosis.

In "Detection of single beta amyloid-protein aggregates in the cerebrospinal fluid of Alzheimer's patients by fluorescence correlation spectroscopy," Dr. D. Riesner, of Heinrich-Heine-Universitat, Dusseldorf, Germany, and colleagues describe how they distinguished 15 people with Alzheimer's from 19 people with other neurological conditions by detecting a form of beta amyloid in cerebrospinal fluid.

"This is an interesting, though very preliminary study," Khachaturian said. "We don't yet know if this testing method can distinguish Alzheimer's disease from other diseases involving amyloid." According to Khachaturian, further testing is needed with larger numbers of people, and should include participants with dementing disorders that are difficult to clinically distinguish from Alzheimer's, such as Lewy Body dementia.

The Alzheimer's Association supports the development of simple, inexpensive and easy-to-administer methods to diagnose Alzheimer's disease. Drawing cerebrospinal fluid requires a lumbar puncture (spinal tap), too cumbersome and expensive a process for routine screening of people for Alzheimer's, according to the Association.

For more information, or to contact Alzheimer's Association, see their website at: www.alz.org