Scientists, federal officials, policymakers, and advocacy groups have argued about the benefit of genetic testing to reveal whether or not an individual is at greater risk for a disease that offers no effective treatment. Enter the growing emergence of risk genes such as apolipoprotein e4 (APOEe4), which increases one's risk for Alzheimer disease (AD), and the debate takes on even greater shades of gray.
Now, scientists have conducted a study to determine whether people with a family history of AD would react with stress and anxiety on the heels of knowing their APOEe4 status. The results, published in the July 16 New England Journal of Medicine, suggest that people — at least those with no history of cognitive impairment or depression — do not feel emotional stress or anxiety when they find out they may develop AD at some time in their future.
These findings challenge a number of assumptions that have filtered into consensus statements written on the heels of APOE genetic testing to identify those who carry one or two copies of the APOe4 allele, said Robert C. Green, MD, MPH, professor of neurology, genetics, and epidemiology at Boston University who designed the REVEAL (Risk Evaluation and Education for Alzheimer's Disease) study to understand the impact of APOE testing in adult children of an AD patient.
“People have a terrible time understanding risk information,” said Dr. Green. “There has been an assumption that knowing one's genotype will trigger stress and anxiety. Many people in the medical profession have also believed that there is no reason to know about your genetic risk for a disease if there is nothing you can do about it.”
Dr. Green set out to test whether it is possible to explain “risk” to people entering a genetic study because of a family history of AD. He collaborated with AD specialists from three different medical centers who had worked on APOEe4 genotyping and designed the study as if the genetic test were a medication. They wanted to quantify the benefits and risks of the intervention.
They randomly assigned 162 study participants — none of whom had have memory problems or depression — to receive genetic counseling with or without the disclosure of their APOEe4 status. They had a baseline measure of anxiety, depression and test-related distress and repeated those assessments at six weeks, six months, and a year after the initial blood draw and counseling.
The scientists found no significant differences on the psychological measures in APOEe4 carriers and non-carriers. (Those who did not have the risk allele did have less test-related distress at the six-week follow-up.)
“We were surprised that there were no differences in stress and anxiety between the two groups,” Dr. Green said. One of the tests is called the “Impact of Events” scale and people with one or two copies of APOEe4 showed “a little distress but nothing clinically significant,” he added. He believes that the genetic counseling to explain what “risk” means and that the test is not predictive of whether anyone will ever get AD is critical to ensuring that the information is not misused.
“APOE testing is fundamentally different than testing for a gene that will determine whether someone gets a disease,” explained Dr. Green. “Testing for Huntington disease [HD], for instance, is definitive — people have more repeats than normal or not — while APOEe4 is a susceptibility factor and that makes all the difference in the world,” he said. “It doesn't take away their hope.”
Dr. Green said that he has withstood criticism over the study by colleagues who thought that it was “dangerous, irresponsible, and would only cause distress and provide no benefit.”
Tanya Zucconi, a study participant who consented to discuss her results, told Neurology Today she would rather have more information than less — a perspective not shared by her brother. Zucconi, whose mother was diagnosed with AD in 2005, learned she carries a copy of the APOEe4 variant.
She said she didn't need the results to begin changing her lifestyle — just in case modifying fat content and intensifying her exercise regime may help alter her life course. She had also purchased long-term health care insurance after her mother's diagnosis and before she entered the study.
In fact, Dr. Green said, people who learned that they carry an e4 allele were five times more likely to purchase long-term health care insurance.
While Dr. Green said that more work is necessary before the consensus statements are rewritten, “we were convinced that people understood the information and used it in an appropriate way.”
KNOWLEDGE OF OTHER DISEASES
Nancy Wexler, PhD, professor of neuropsychology at Columbia University, who was an organizer of the team that discovered the Huntington disease gene — the mutation is a characteristic expansion of a nucleotide triplet repeat in the DNA that encodes or the protein, huntingtin — said she has been studying the effects of genetic testing since the 1980s when the first genetic markers became available to identify the disease. She pointed out how difficult it is with a test that is predictive and wondered how people would deal with the probability of risk.
“The APOE test is not predictive of whether someone will get Alzheimer disease or not,” she said. “People don't understand probability. They have no real sense of their odds. Do they really understand that having one or two copies of e4 is not a certainty that they will get the disease?”
Dr. Wexler, who is president of the Hereditary Disease Foundation and whose mother had HD, said that 10 percent of people with a family history of HD get genetic testing, and that figure has not changed over the last 15 years. Testing for HD poses its own unique problems, she said, because it is an expansion of DNA segments that lead to illness. And knowing that you have expanded repeats does not provide a crystal ball to say when that person will get sick. The onset of symptoms could span decades.
She said that people can't get tested without a lengthy neuropsychological evaluation and counseling. Even then, “people can get totally confused because a genetic test is completely different from a clinical diagnosis.” She does not believe in the importance of genetic testing for conditions where there are no treatments, as is the case for HD. “There is nothing out there to be tested for,” she said. “I wish there were.”
Daniel van Kammen, MD, PhD, chief medical officer of the CHDI Foundation, a private nonprofit research organization developing therapies for Huntington disease, said that there had been a concern that genetic testing would lead to suicides in people who tested positive for the expanded CAG repeats (HD gene), which does not seem to be the case.
“The major current concerns are about people at risk who can continue to hope that they would be free of the disease (50 percent chance), only as long as they don't know their gene status (100 percent positive or negative),” he said. “Some people do want to find out because it assists them in planning their future. Others want to participate in research that may lead to finding more effective treatments perhaps in their own lifetime, or for the benefit of the next generation.”
“The issue today is whether testing will ultimately be of benefit to an individual who may feel in limbo not knowing,” he said. “It is a very personal and complex decision.”
Dr. Wexler doesn't agree. “The diagnosis is fatal but the information can be too,” she said. “In a survey of 178 genetic testing centers around the world, Canadian scientists reported in a 1999 paper in the American Journal of Human Genetics that 44 out of 6,000 people tested for HD had a catastrophic reaction to the news. Five committed suicide, 19 attempted suicide, and 20 others were hospitalized for psychiatric problems on the heels of the test results. Even though this predictive test is optional, it was associated with severe consequences. This information is certainly not benign.”
FINDING THE AD RISK GENE
It has already been 15 years since APOEe4 was identified as the first risk gene for late-onset Alzheimer disease. The discovery of the link between APOEe4 and Alzheimer disease by Allen D. Roses, MD, and his colleagues at Duke University, remains the strongest genetic risk factor to date. People with one copy of the e4 variant are three to four times at higher risk for AD than people without the allele; those with two copies are more than eight times the risk. Unlike mutations that guarantee a disease, there are many people who carry an e4 allele who will never develop AD. And there are also people without e4 who will get AD.