Posted 4 June 2007

ApoE Genetic Testing To Estimate a Person's Risk of Developing AD
By Gabrielle Strobel

Genetic and epidemiologic studies have confirmed ApoE to be the strongest known genetic risk factor for common late-onset AD. Having inherited a single ApoE ε4 variant increases one's risk of developing AD by a factor of three in men and four in women, and having two copies increases risk up to 15-fold compared to persons without the ε4 variant. ApoE testing is not clinically available to predict AD risk in healthy people, though it is sometimes offered as part of a diagnosis of a person who already has AD symptoms. In academic research settings, ApoE susceptibility testing is being studied in people who have a parent with AD.

ApoE testing is relevant to a much larger segment of society than testing for the rare mutations in the PS1, PS2, and APP genes that cause early-onset familial AD in a deterministic fashion (for the latter, see Genetic Testing and Counseling for Early-onset Familial Alzheimer Disease). In contrast to the deterministic mutations, ApoE is a "susceptibility" polymorphism. This means that the presence of one or two ε4 alleles increases the risk but does not guarantee that someone will develop AD. Almost all deterministic mutation carriers develop mid-life AD, but many people with ApoE ε4 do not. Conversely, many people who have AD carry no ApoE ε4 gene variant.

Consequently, interpreting ApoE genotype information is more complex than when a person has inherited a deterministic mutation. Essentially, it requires that the doctor and the test-taker grapple with graded probabilities. For most people, the overall risk equation is a mix of genotype, gender, ethnicity, family history, and age. A challenge for the physician, then, is to help people understand what they are to make of, for example, a 40 percent remaining lifetime risk of developing AD when they are 48. Research has shown that many people in the general population have difficulty interpreting probabilistic risk assessments. Not all physicians have the training to calculate and communicate risk. For these reasons, it is wise to conduct genetic testing through a qualified medical center.

Soon after ApoE was discovered as an AD risk gene in 1993, a genetic test became available. Concern over widespread testing among a poorly informed populace prompted discussion among professional groups, and they put the brakes on its routine use for the time being. In the absence of a preventive treatment, these groups warned, rushing headlong into genetic testing would be unethical. Between 1995 and 1997, working groups drawn from the National Institute on Aging, the Alzheimer's Association, the American College of Medical Genetics, and the American Society of Human Genetics threw their weight behind a message of caution. They recommended against ApoE testing to predict future AD in healthy people. They felt that science still knew too little about ApoE genotyping to weigh the benefits of knowing against its downsides. How about genetic privacy? Would the person's insurability, social standing, psychological health suffer? What would genetic counselors have to do to cushion the blow? Who would even want to know their ApoE status? Clearly, more study was needed.

To shed more light on ApoE susceptibility testing, in 1999 the National Institutes of Health funded a multicenter study headed by Robert C. Green of Boston University, called Risk Evaluation and Education for Alzheimer's Disease (REVEAL). In the meantime, matters have advanced on the therapeutic front, as well. Mechanism-based experimental drugs are wending their way through the clinical trial process. If any of them prove their worth, public demand for ApoE testing may increase.

For its part, the REVEAL Study has yielded some of the data needed to guide the process and associated counseling. The first phase of the REVEAL Study enrolled 162 healthy adult children of people with AD. It offered half of them genetic counseling based only on their family history and gender; the other half received counseling with ApoE testing. Not all results are published yet, but here are the main findings to date:

Why Do People Choose ApoE Genotyping? The top reasons people cited grouped around altruism and coping. People wanted to arrange personal affairs and long-term care; they wanted to contribute to research and hoped that treatments would come online in time. They wanted to prepare family members, to do things sooner than planned, and hoped for relief if they were ApoE4-negative. People knew that knowing their ApoE status would not improve their medical care but opted for the test because they thought they'd be better able to plan and to cope.

Who Chooses to Find Out? People younger than 60 and college-educated people wanted to know, and women did so more than men (a preponderance of women also turned up in several international studies of HD predictive testing). Of the people the scientists contacted, a quarter chose to participate; of the ones who heard about the study and contacted the study coordinators themselves, 64 percent did. Self-selection strongly showed its face, as it does with predictive testing for deterministic diseases.

Genes as Destiny? In the REVEAL study, people placed great stock—perhaps too much—in genetic information. There were two groups who had the same total risk, but one had that level of risk with an ApoE4-negative genetic test result. These latter people perceived their risk as less worrisome and expressed relief because they were genetically "off the hook" even though their total family- and gender-based risk was actually identical to that of the second group who did not have the ApoE information.

Insurance: In the year after the study ended, few participants made changes to their health, life, or disability insurance, but the ApoE4 carriers tended to take out long-term care insurance. Future discrimination by insurers is an area that may require public policy protections.

Health Behavior: A constant drumbeat of health reports urging people to eat well and exercise has shown little efficacy, as rates of obesity, diabetes, and sedentary lifestyle inexorably increase. In this group, however, participants who received high-risk estimates at least self-reported certain changes, such as dietary improvements and exercise.

Psychological Consequences: Fears of depression and hopelessness were a major driving force behind the field's hesitation to embrace genetic testing. The REVEAL study has not found evidence to support this. Knowing their ApoE genotype did not hurt participants' psychological well-being. Participants already were anxious about their risk because of their parents' AD; those without ApoE4 expressed relief, those with it expressed more distress initially but not at later follow-up times.

Genetic Counseling: The counseling protocol used in REVEAL works but is too time-consuming to be practical if ApoE susceptibility testing were to become widely available. A second phase of the REVEAL study is testing whether condensed education and counseling would adequately support risk assessment and genotyping. The abbreviated approach did away with the personal pre-test sessions mandated by widely used, extensive genetic counseling protocols and instead mailed out an educational brochure. Early results suggest that people who received risk assessment through the condensed protocol did just as well as those who were in the longer protocol.

In the future, demand for genetic risk assessment with ApoE disclosure will likely grow, especially if disease-modifying drugs are developed and people with higher risk wish to use them presymptomatically. If any of the experimental drugs now undergoing clinical testing prove to work better or worse in people who are ApoE ε4 positive, such evidence would add further incentive because then the ApoE test result would help the physician choose the right medication for a given patient. In addition, societal expectations are changing as we enter the era of "personalized medicine." Increasingly, as shown in the REVEAL Study, healthy adults view genetic testing as valuable for coping with the fears they already have from managing their parent's disease.