Genetic testing for Alzheimer disease (AD) should be available to anyone who wants it, but it is most reliable and informative for members of families with a history of the rare, early-onset form of the disease, according to new practice guidelines developed by members of the American College of Medical Genetics and the National Society of Genetic Counselors.
Testing for early-onset familial AD should not be offered to children, according to the authors, who also discourage direct-to-consumer testing for the apolipoprotein (APOE) gene since it predicts risk so poorly. And all genetic testing for AD should be accompanied by genetic counseling with personnel trained to discuss the motivations for testing, the limits and implications of the results, and the potential for grief, depression, and other psychological reactions.
“What these recommendations do is highlight the need for individualized counseling,” said John K. Fink, MD, professor of neurology and director of the Neurogenetic Disorders Program at the University of Michigan, who was not involved with these guidelines. “Counseling must be individualized for the patient and the family, and this report provides a framework for the issues involved.”
The guidelines, published in the June issue of Genetics in Medicine, clearly distinguish between testing for early-onset familial AD, caused by dominantly inherited mutations for presenilin-1 (PS1), presenilin-2 (PS2), and amyloid precursor protein (APP), and the far more common sporadic AD, in which risk may be increased by possessing one or two ε4 alleles of the APOE gene.
People who discover that they carry a gene for early-onset familial AD, which usually produces symptoms by the age of 60, have been known to experience severe psychological distress. Jack Kevorkian's first assisted suicide, in 1990, involved Janet Adkins, a 54-year-old Oregon right-to-die advocate with early-onset AD.
THE RIGHT TO KNOW
Thomas D. Bird, MD, a senior author of the guidelines, believes people who undergo such testing are entitled to know the results, but, as the new guidelines indicate, they deserve attentive counseling.
“I'm not aware of anyone who tells people, don't have testing done,” said Dr. Bird, professor of neurology and chief of neurogenetics at the University of Washington in Seattle. “But I think the thrust of genetic counseling should be education and information.”
Knowledge of APOE genotype status has not been shown to cause psychological distress, probably because the APOE ε4 allele is neither necessary nor sufficient to cause the disease, he said.
The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study found that when 162 asymptomatic people who had a parent with sporadic AD were randomized, those who received knowledge of their APOE status “did not have greater anxiety, depression, or test-related distress than those who were assigned to undergo risk assessment without APOE disclosure,” according to a 2009 report in The New England Journal of Medicine.
The REVEAL study has now disclosed APOE status to nearly 1,000 individuals with results that support these initial findings, said Robert C. Green, MD, MPH, the principal investigator and director of the REVEAL study. Nevertheless, he believes disclosing the results of APOE status should be handled with caution.
“In the absence of preventative or disease-modifying treatments, I do not think that APOE disclosure should be routine among unaffected family members,” said Dr. Green, a geneticist and neurologist at Brigham and Women's Hospital and Harvard Medical School. “However, I do think that people have a right to know their risks if they wish to, and that dealing with patients who have risk markers, be they genetic, chemical biomarkers, imaging biomarkers, or some combination of these, will be important for patient care in the future.”
The guidelines, which follow those for genetic testing for Huntington disease, do not deviate significantly from standard practice, said the lead author of the guidelines Jill S. Goldman, MS, MPhil, genetic counselor at the Taub Institute at Columbia University in New York. “If you went into any Alzheimer's research center, this probably would be common practice, but your general neurologist who doesn't deal with genetic testing every day might not know how to go about this,” she said. “They may be used to ordering genetic tests for diagnostic purposes, since lots of neurological diseases have a genetic component, but they probably don't deal with pre-symptomatic people very often. Or they may have patients who go to websites and show up with a report on APOE and ask, what does this mean? The guidelines provide a tool to use in such situations.”
Christopher M. Filley, MD, director of the behavioral neurology section and professor of neurology and psychiatry at the University of Colorado School of Medicine, and chief of neurology at the Denver VA Medical Center, agrees with that assessment. “Many of the recommendations are routinely followed already, but these guidelines offer a reasonable approach that can assist neurologists dealing with this issue,” he said. “I think these guidelines are helpful in codifying clinical practice regarding genetic counseling and testing for Alzheimer disease.”
SOME DON'T WANT DISCLOSURE
Given the opportunity to find out if they carry genes for early-onset AD, most people decline, according to Goldman. She is currently involved in the DIAN study (Dominantly Inherited Alzheimer's Disease Network), in which people at risk for carrying a mutation in PS1, PS2, or APP are studied in an effort to detect the earliest possible symptoms. All participants have the option to find out their gene status, “but almost nobody does,” Goldman said. “Of those who chose to find out, the majority do so for reproductive information. They might want to do pre-implantation genetic diagnosis, for example, or they might want to give the information to their children. Some people do say, ‘I think about this every day,’ or, ‘I think it would be better for me to know and plan accordingly than not to know.’ Those are legitimate reasons as long as they're facing reality.”
Until now genetic testing for the APOE ε4 allele has been deemed pointless since possessing the gene merely increases risk somewhat, and no treatments or lifestyle modifications were known to alter the course of the disease.
As treatments and lifestyle modifications to fight Alzheimer disease are discovered, the guidelines will undoubtedly be adjusted, according to Wylie Burke, MD, PhD, one of the authors of the new guidelines.
“From an ethical perspective, the game changer would be interventions that are either specific to or much more valuable in people with a particular genotype,” said Dr. Burke, professor and chair of the department of bioethics and humanities at the University of Washington. “If we found that drug X reduced the risk of Alzheimer disease in people who had the APOE ε4 allele, but not in other people, we might even recommend testing to be sure to identify people who could benefit. So, the current recommendations should be re-evaluated and updated appropriately as new data are available.”
WHEN DISCLOSURE LEADS TO DISTRESS
An early experience with genetic testing for early-onset AD caused Lars Lannfelt, MD, PhD, the Swedish neurologist who had discovered the amyloid precursor protein (APP) mutation, to advise against it. In 1992, after discovering the APP mutation in two Swedish families, Dr. Lannfelt and his colleagues conducted genetic testing on 21 family members. Eighteen did not want to know their results, but three did. As the researchers reported in 1995 in the American Journal of Human Genetics, all three underwent the same type of genetic counseling provided for children of a parent who has Huntington disease, and two of the three were free of the mutation. The youngest who tested positive “reacted with anxiety, sorrow, depressive feelings, and, for a period of one month, suicidal thoughts,” the authors reported. The patient eventually died of the disease, and Dr. Lannfelt and his colleagues concluded that they would have served this patient better through counseling without genetic testing. “Pre-symptomatic testing for AD may in the future become widespread,” they wrote. “The experience we describe here suggests that such testing needs to be handled with exquisite care.”
However, a study of 12 people who learned they carried a mutation for early-onset familial AD found that two reported moderate anxiety, and one reported moderate depression. “Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown,” concluded the authors of the study, which was reported in 2001 in the Archives of Neurology.
Goldman JS, Hahn SE, Bird T, et al. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med
Lannfelt L, Axelman K, Basun H, et al. Genetic counseling in a Swedish Alzheimer family with amyloid precursor protein mutation. Am J Hum Genet
Steinbart EJ, Smith CO, Bird TD, et al. Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia. Arch Neurol
Green RC, Roberts JS, Farrer LA, et al, for the REVEAL Study Group. Disclosure of APOE genotype for risk of Alzheimer's disease. N Engl J Med
©2011 American Academy of Neurology
Linnenbringer E, Roberts JS, Green RC, et al. “I know what you told me, but this is what I think:” Perceived risk of Alzheimer disease among individuals who accurately recall their genetics-based risk estimate. Genet Med
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