Dementia of the Alzheimer Type

Signs of Alzheimer's Visible in Brain Before Symptoms Set In, Researchers Find

By Susan Jeffrey
The Medical Post, April 2, 1996

PHOENIX - People at genetic risk for late-onset Alzheimer's disease (AD) show functional changes in the same brain areas affected by the disease even before they have symptoms, a new study shows.

The ability to detect and follow subclinical disease could make positron emission tomography (PET) scanning an important tool in testing therapies to treat or even prevent the devastating disease.

The paper, a collaboration of researchers at the University of Arizona, Arizona State University, the Mayo Clinics in Scottsdale and Rochester, Minn., and the University of Michigan, was published in the March 21,1996 issue of The New England Journal of Medicine.

Their findings also add to the weight of evidence that the e4 allele of the apolipoprotein E gene raises the risk for developing AD.

"In the last three years, (the association of AD and the e4 allele) has been confirmed in 100 clinics, but almost all of the studies have started with older people with and without Alzheimer's disease and then looked back at their genes," said Dr. Eric Reiman, associate professor of psychiatry at the University of Arizona and scientific director of the PET centre at Good Samaritan Regional Medical Center in Phoenix.

"It was argued that really to confirm the risk, you needed to start with people without symptoms and follow them over time, to see who goes on to develop the disorder," said Dr. Reiman in an interview. "As you can imagine that could take many years."

PET measures of reduction in glucose metabolism in brain areas characteristically affected by AD could reduce the time it takes to track progression of the disease.

Dr. Serge Gauthier, director of the McGill Centre for Studies in Aging and professor of neurology, neurosurgery, psychiatry and medicine at McGill University, called the new study "significant."

"We are slowly building a consensus on how to measure progression of the disease, starting measurements even before you get symptoms," Dr. Gauthier said. "This is one step forward in giving us a biological variable we can follow during stabilization treatments."

A number of treatments are now being tested, he added, including estrogen supplements, low-dose prednisone, cholesterol modifying drugs and nonsteroidal anti-inflammatory drugs.

The researchers also found subjects with the highest risk of AD -- those with two copies of the e4 allele -- showed reductions in glucose metabolism in other areas of the brain known to deteriorate with normal aging.

"These changes in additional regions sensitive to aging supports the possibility this gene may be an aging gene," Dr. Reiman said. "We propose that the apo e4 gene speeds up certain aging processes, and the apo e2 gene slows them down."

Their hypothesis springs from some of the data now being generated about these genotypes, he said. Individuals with the e4 allele not only have an increased risk of AD, but they get it at an earlier age, they have a higher risk of coronary artery disease, another age-related disorder, and a shorter lifespan overall. Those with the e2 allele are generally less affected by these age-related disorders, get them later if at all, and have a longer lifespan.

In the study, 235 volunteers between 50 and 65 years of age, with a self-reported family history of AD but no cognitive impairment, were screened for their apo E genotype.

Neurologic and psychiatric evaluations, neuropsychological testing, magnetic resonance imaging and PET studies were done on 11 subjects homozygous for the e4 allele and 22 subjects without the e4 allele matched for age, sex and level of education.

They used a new mapping software and the PET and magnetic resonance imaging (MRI) images to generate an aggregate surface-projection map of regional rates of glucose metabolism in the two groups.

The e4 homozygotes were found to have reduced rates of glucose metabolism in the same brain areas as subjects with AD studied previously -- the posterior cingulate, parietal, temporal and prefrontal regions.

While there was some overlap, he said, those without the e4 allele did not show the same changes.

As significant as these findings may be as a potential research tool, Dr. Reiman emphasized that apo E genotyping and this PET technique should not be used to predict an individual's risk for developing AD.

"These tests do not tell us for sure whether or not we're going to develop this frightening illness. They don't tell us when we might develop symptoms -- that can vary by 20 years -- and they don't tell us yet what we might do about it.

"Certainly these tests should not be used in healthy people to determine eligibility for insurance, for employment, for health care coverage."

In this study, subjects weren't told which category they fell into.

"It's relevance, I hope, and what we're excited about, is being able to use this to help in the effort to find a way to treat and prevent the disorder," he added.

In an editorial accompanying the publication, Dr. Edward Campion, deputy editor of the NEJM, agreed. While he called their findings "remarkable," Dr. Campion wrote, "For now, the implications of the preclinical findings in Alzheimer's disease are for research, not clinical practice.

"Reiman's analysis aggregated subtle changes on PET scans, and compared group averages. This is not a test for Alzheimer's disease."

Dr. Reiman and colleagues plan to use this technique to follow subjects with no copies, one copy and two copies of the e4 allele over time to further define its association with disease development.

Copyright 1996 Maclean Hunter Publishing Limited
Reprinted with permission.

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