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DURHAM, N.C. -- For a long time, the only way to determine
if Alzheimer's disease patients actually had the disorder was
to examine their brains after death. But a new study shows that
testing for a certain gene type can tell physicians which
patients are almost certain to have Alzheimer's disease.

The study conducted by researchers at Duke University
Medical Center is the first to look at the genetics of a group
of 67 patients diagnosed with Alzheimer's and whose brains were
examined after death. The findings were published in the July
13 issue of The Lancet.

The scientists found that every patient who had the
Alzheimer's susceptibility gene, known as apolipoprotein E4
(APOE4), had the disease's telltale neurofibrillary plaques and
tangles. That means testing for APOE4 in these patients was
accurate in predicting which patients had Alzheimer's.

Such a test can, therefore, accurately diagnose the disease
in the majority of patients thought to have the disorder, said
Dr. Allen Roses, the study's principal investigator. Up to 65
percent of Alzheimer's patients are believed to carry the APOE4
gene.

Every year, hundreds of thousands of people are diagnosed
with "possible" Alzheimer's disease. But the disease is
difficult to separate, clinically, from other memory disorders,
and to date, no test has been readily available to help
neurologists make an accurate diagnosis.

"This demonstrates the value of genetic testing in
differentiating between most of the patients who have the
disease, and those who may be suffering from another form of
dementia," Roses said in an interview.

"An accurate diagnosis is critical in deciding how to manage
patients, and to determine which drugs work in Alzheimer's
disease and which work in non-AD patients," he said.

Roses added that because this study was small, "more
extensive studies with many series will be needed to determine
accuracy with confidence limits."

The study was funded by the National Institute on Aging and
the Alzheimer's Association.

In 1993, Roses and his colleagues found that of the three
different gene types for APOE (known as the e2, e3, and e4
alleles), e4 was associated with an increased risk of
developing Alzheimer's disease. But accurate estimates of the
gene_s diagnostic effectiveness could not be made without
detailed patient information, including brain autopsies,
according to Dr. Ann Saunders, lead author of the study.

So the Duke team looked back at patients who had been
treated at Duke's Memory Disorders Clinic, from the time of
diagnosis by a staff neurologist through to death and autopsy.
Some of these patients were followed over a decade. All of the
67 patients were diagnosed as probable Alzheimer's at the time
of their death.

Autopsy results showed that 10 patients (15%) did not have
Alzheimer's when their brains were examined. None of the
non-Alzheimer's patients had an e4 allele, and 25% of the
Alzheimer's patients also did not carry an e4 allele.

"If you have a patient with clinical Alzheimer's disease who
has an e4 allele, it is highly probable that they actually have
Alzheimer's. In this initial study, it was 100%," Roses said.
"Our analyses resulted in two groups; the first contains 75% of
the Alzheimer's patients who have an e4, and the second 25% of
the Alzheimer's patients and all the non-Alzheimer's who do not
have an e4."

Therefore, genotyping is useful in those Alzheimer's
patients who have an e4 allele, but is not useful in those who
do not. "In a clinical setting, then, APOE genotyping will
identify three of four patients who have the disease," Saunders
said. "It is no help with patients who do not have an e4."

"This is the first actual measurement of genotyping in a
series that could evaluate misdiagnoses. Recent consensus
statements were based on variable estimates of the correct
diagnosis of Alzheimer's disease, not autopsy confirmations,"
she said.

The finding is important for several reasons, according to
the researchers.

One is that the finding demonstrates a substantial
percentage of people being diagnosed with the disease actually
suffer from something else -- which, may, in fact, be as
untreatable as Alzheimer's. This finding confirms the rough
estimate long made by neurologists that 15 percent of patients
diagnosed with Alzheimer's will not actually have the disease,
Roses said. "But it shifts the non-Alzheimer's patients into a
patient group that can be defined during life. This is a useful
diagnostic test, but it also has tremendous implications for
evaluating drug trials."

This second application can change the way researchers
interpret therapeutic trials, Roses added. The effect of
experimental medications can be tested on the two different
groups and compared, he said. "A drug that works in the non-e4
group, as has been reported by others for Tacrine, may actually
be working in the non-AD patients in that group -- still
important, but not what has been concluded. An effective drug
for Alzheimer's could be anticipated to work better in the e4
group enriched for Alzheimer's disease, but perhaps less so in
the non-e4 group which contains some Alzheimer's patients and
the non-Alzheimer's patients."