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Patients' Brains Show Accuracy of Alzheimer's Disease Gene Typing 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 mis-diagnoses. 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."
Based on the Alzheimer s disease genetic findings, Duke licensed the patent to a biotech company, Athena Neurosciences, to develop a genetic test to help doctors diagnose a patient suspected of having Alzheimer s disease. In April, that test was made available to physicians, with the understanding that it is not to be used as a predictive test in asymptomatic people. Royalties from the sale of the test go to Duke University Medical Center, Roses and other researchers and the Joseph Bryan Scholars Fund.
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