DENVER—Do the children of persons with Alzheimer’s disease want to know if they, too, are at risk for the disease? And what are their reasons for wanting to know? Both answers may be surprising. Two related studies from Boston University School of Medicine examined who would elect to pursue genetic testing and the impact of this risk assessment.

These questions were addressed as part of the NIH-funded REVEAL Study (Risk Evaluation and Education for Alzheimer’s disease) in which cognitively normal adult children of patients with Alzheimer’s disease were offered risk assessment, including genetic susceptibility testing with apolipoprotein E (APOE) genotyping.

To determine the characteristics of those most likely to proceed with genetic testing, researchers examined the number of REVEAL study subjects who proceeded from an initial phone interview to actual blood draw and disclosure. “At the present, when we offer people insights into their risk of developing Alzheimer’s disease based on APOE genotyping there isn’t very much they can do to change their risk,” remarked Robert C. Green, MD, MPH, director of the study. “Nonetheless, people want to know.”

In these reports of preliminary data from the REVEAL Study, 175 eligible subjects in Boston, New York City, and Cleveland were offered the opportunity to participate in the study, in which risk assessment and APOE genotyping would be disclosed. Of these, 94 (54%) chose to participate in the telephone interview, 63 (67% of those interviewed) continued to the education session, 47 (75% of those attending the education session) continued to blood draw, and 40 (85% of those who had blood draw) continued to genotype disclosure. Overall, 40 of the original 175 eligible subjects (23%) continued through the entire protocol to seek APOE genotype disclosure. Age, sex, non-white ethnicity, marital status, number of affected relatives, and subjective worry about developing Alzheimer’s disease had little bearing on continuation through the study; years of education was the only characteristic to be positively associated.

What Dr. Green found most surprising was the number of people interested in participating in a study in which they would learn their genetic risk. “More than 20% of the people we contacted proceeded through to the blood draw step, which was a surprise to us.” These participants continued with the study despite the fact that the protocol was very clear about the limitations of the testing and that the results conferred approximate risks, not definitive information. “Here we have a genetic test that’s not a very precise measure of disease risk, for a disorder in which there is no cure, and yet 23% of a systematically contacted population were serious enough to come in, sign up, and have their blood drawn. To me, this is a remarkable finding, because when you think that there will be 14 to 20 million people with Alzheimer’s disease in the next 50 years—and [many of] those people are going to have adult children— that means there are potentially millions of people who might be interested in genetic susceptibility testing.” He made his remarks at the 54th Annual Meeting of the American Academy of Neurology.

Dr. Green is quick to point out that these participants were recruited from families who had already volunteered to be part of research registries, so they were undoubtedly more motivated than persons in the general population. But the figure remains remarkable, he believes, especially in comparison to the Huntington’s disease experience. “For Huntington’s disease, a test was developed that predicted with certainty who would be affected by the disease, and relatively few people came forward to request it. I think part of the difference is that it’s reassuring to get risk figures without certainty. It gives you a way out,” said Dr. Green, who is an Associate Professor in the Department of Neurology at Boston University School of Medicine.

The researchers also examined reasons given by REVEAL Study participants as to why they chose to undergo risk assessment. “Doctors and genetic counselors reflect their priorities and sometimes have strong opinions about why people should or should not seek risk assessment. But people have their own reasons for wanting risk assessment—and it’s not always wanting to cure the disease or intervene medically. Sometimes it’s about being able to prepare themselves and their families mentally and emotionally for the potential impact on their lives,” observed Dr. Scott Roberts, a clinical psychologist and a co-investigator in the REVEAL Study.

The researchers examined 12 reasons presented to 218 participants (74% female; 93% white; mean age, 53; mean years of education, 16), the vast majority of whom eventually decided to pursue genetic susceptibility testing for Alzheimer’s disease. More than 60% of participants agreed with nine of the 12 reasons offered for pursuing genetic risk assessment for Alzheimer’s disease. The majority of participants (94%) cited the desire to participate in and contribute to Alzheimer’s disease research as motivation. Other reasons given for pursuing genetic testing were the need to arrange personal affairs (87%), the hope that an effective treatment will be developed (85%), the need to arrange long-term care (82%), the desire to do things sooner than had been planned (78%), the need to prepare family members for Alzheimer’s disease (77%), and the need to learn information that may eventually be useful for family planning (70%). Endorsement of the need to prepare family members for Alzheimer’s disease was the best predictor of who actually went on to have their blood drawn. On average, women endorsed more reasons for testing than men.

“We were very impressed with people’s altruism. You could argue that since there’s no cure, they shouldn’t want to obtain genetic testing and risk assessment. But, in fact, they wanted to refine their sense of risk for reasons of their own … to have a better understanding of their possible future, to plan their life a little better, to prepare their family, to put finances in order,” Dr. Green related. “I think this goes to the very important issue of autonomy: these individuals felt that there were reasons important enough for them to come in and stick their arm out and get a potentially frightening result. As long as we can present information accurately and safely, I believe that we must respect their reasons.”

With the use of a careful protocol and sensible educational and counseling efforts, Dr. Green believes people can be safely informed about their disease risk. “The need to understand personal risk will only increase as new treatments become available in the future. Some of these treatments may have serious side effects or may well be very expensive, and in either of these cases it will be important to assess who is at high risk and who is at low risk. By doing susceptibility genotyping with careful education and counseling, we are doing something much more akin to what doctors traditionally do with patients when they assess risk of heart disease or cancer than what genetic counselors traditionally do with deterministic genetic testing.”

In designing the first study using a susceptibility gene to provide information to relatively young people about their future risk of developing an age-associated neurodegenerative disease, the research team had to pilot a new paradigm for delivering risk information. “We put considerable thought and effort into creating this paradigm,” stated principal investigator of the Cornell University study site Dr. Norman Relkin, MD, PhD, Assistant Professor, Department of Neurology and Neuroscience. “We needed to address a number of issues for which there were few clear precedents. How do you convey this type of information to those at risk? What terms should you use to communicate risk? Is the magnitude of the risk better appreciated from visual aids? How much time should be spent in the counseling process? What type of emotional fallout should you worry about? How do you monitor people’s reactions to this type of information?”

Safety is clearly a concern, since participants could theoretically misunderstand risk information or have adverse psychological reactions to such information. Dr. Green believes his team has adequately protected the safety of the study subjects. “Some individuals do express concerns that they would be traumatized or even suicidal if they find out that their risk is high, but we have approached this with a great deal of screening and follow-up to ensure safety. In the current protocol we are also using trained genetic counselors to communicate the risk assessment and evaluate the reactions of the participants.

The REVEAL Study protocol follows study subjects for one year after disclosure to determine if they actually change their health habits, insurance, or other aspects of their life based on the risk assessment they received. “This study points to the difference between survey data and real-life data,” Dr. Green emphasized.

Given the health crisis Alzheimer’s disease will present, the researchers believe genetic testing will have powerful health implications for the future. “Everyone understands APOE is not the sole determinant of whether an individual will develop Alzheimer’s, but it is a very important susceptibility marker,” Dr. Green stressed. “We are discovering hundreds of other susceptibility markers for hundreds of other diseases, and we will need to have processes in place to deal with communicating risk information based on genetic susceptibility testing. Our hope is that the results of the REVEAL Study will inform policy debates and future guidelines about integrating risk information into human health care as the genetic basis of disease is unraveled.”

NR

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