Part 2 of two.

With Alzheimer’s secondary prevention trials now underway, the question of how best to tell people about their AD risk has arrived. The ongoing Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial uses a protocol similar to traditional genetic counseling methods to inform approximately 1,000 people about their brain amyloid status (see Part 1 of this story); however, the soon-to-start Alzheimer’s Prevention Initiative’s ApoE4 trial focuses on genetic risk for late-onset AD and will therefore draw on an even larger pool of potential participants. Faced with the challenge of finding and communicating risk to many thousands of people, API researchers have had to tailor classic in-person disclosure models making greater use of technology such as computers and telephones. At the Alzheimer's Association International Conference 2015, held last month in Washington, D.C., Jessica Langbaum of Banner Alzheimer’s Institute in Phoenix detailed the new protocol. She noted that the API trial will provide the first large-scale test of whether such remote methods can work as well as established, face-to-face genetic counseling protocols.

The established protocols first proved themselves in the cancer field, where genetic counselors are more plentiful than at Alzheimer’s clinics. Nonetheless, in D.C., Angela Bradbury of the University of Pennsylvania, Philadelphia, pointed out that breast cancer researchers, as well, have since moved toward remote disclosure. Few studies have compared the outcomes against the older methods, she stressed. “We don’t know the impact of these alternative delivery models,” she told Alzforum. A handful of studies have reported no difference in anxiety or depression among participants counseled about their cancer risk remotely versus face-to-face, but fewer people chose to proceed with genetic testing when the initial meeting with a counselor occurred remotely (see Hilgart et al., 2012; Schwartz et al., 2014; Kinney et al., 2014). Bradbury is collaborating with API researchers to help test such newer methods.

Traditional disclosure methods have a good track record in AD. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study led by Robert Green of Brigham and Women’s Hospital, Boston, reported that middle-aged people informed of their ApoE genotype handled the information without undue distress or long-term negative effects (see Jun 2007 webinarJul 2009 news). Subsequent REVEAL studies have examined additional issues, such as whether the information is more disturbing to people who already have mild cognitive impairment and thus higher risk of progression. The results were similarly positive (see Aug 2012 conference news).

In D.C., Scott Roberts of the University of Michigan, Ann Arbor, updated the audience on what REVEAL says about ApoE4 homozygotes, who inherit about 12 times the risk of AD that non-carriers do. Researchers pooled data from the 28 homozygotes who took part in the first three REVEAL studies. As a group, they reported worrying about the test results more than heterozygotes in the first few weeks after disclosure, but clinical measures of depression and anxiety did not budge. In addition, people with two copies of ApoE4 were more likely than heterozygotes to report that they made lifestyle changes in response to learning the news, such as improving their diet, taking vitamins or supplements, or starting an exercise program.

Will High-Tech Disclosures Work?
The REVEAL studies had limitations, however. The number of ApoE4 homozygotes was very small, and participants were a highly educated group who had chosen to learn their status, so the studies may not reflect the general population. Clinicians at Banner expect to get more definitive data on the effects of disclosure soon. They are preparing to enroll 1,300 people who carry two copies of the ApoE4 allele for the first API ApoE4 prevention trial (see Jul 2014 conference news). Potential participants must learn their ApoE genotype to be considered for the trial. Some may already know it through testing done at a memory clinic, through a direct-to-consumer service, or at a cardiac clinic (the latter because ApoE4 boosts the risk of coronary artery disease). But for the majority who do not, Banner offers the API ApoE4 Genetic Testing and Counseling Program. This sub-study will examine the impact of disclosure and the best way to go about it, Langbaum said. To compare the effect of disclosure on different genotypes, the study will include ApoE4 homozygotes, heterozygotes, and non-carriers, although only the former are candidates for the intervention trial.

First, the researchers need to find potential participants. Only 1 to 2 percent of the population carry two copies of ApoE4, so trial personnel will need to genotype upward of 60,000 people to identify enough carriers. Researchers will reach some people through memory clinics, but most potential participants will come from the Alzheimer’s Prevention Registry. This online registry currently has more than 135,000 members, who have signed up to receive information about Alzheimer’s research and future trials. After the Genetic Testing and Counseling Program receives regulatory approval, which may occur this fall, registry members between the ages of 55 and 75 will receive an invitation to donate DNA, Langbaum said.

Those who express interest will be asked to first complete a brief, interactive module about genetic testing online or over the phone with a health educator at Banner. “We recognize that not everybody has Internet access or wants to do this online,” Langbaum said. The module will inform participants that Banner will use the genotyping results to match people to future trials, but it will not disclose the findings to participants. It would not be practical or ethical to try to disclose genetic status to everyone, Langbaum noted. 

People who choose to proceed will sign a consent form and then receive a cheek-swab kit through the mail. They can collect their own DNA at home, then mail it to a central lab for analysis. Langbaum noted that her team encountered unexpected hurdles while setting up this process. Because many states consider DNA testing to be a practice of medicine, a doctor’s approval is required to mail samples across some state lines. To comply with regulations, API contracted with medical providers in those states to review orders that come in through the website and approve the cheek-swab kits. “There are other initiatives looking at doing cheek swabs by mail, so this experience can be a lesson for all,” Langbaum told Alzforum.

After genotyping, API will invite about 3,000 DNA donors in the United States, and additional participants overseas, to learn their ApoE status. In Europe, participants will go to a clinic to meet face-to-face with genetic counselors to get their results, but U.S. participants will be told either by phone or videoconference from a centralized group based at the University of Pennsylvania. This format will allow researchers to directly compare the effects of disclosure by phone, videoconference, or in person. “No study has yet compared all three. This is really novel,” Langbaum said. She noted that this protocol modifies the traditional genetic-testing model used in oncology, since participants will receive pre-test counseling remotely, take part in genotyping through the mail, and in many cases learn their results via technology. “We need to think about ways to scale up disclosure to a real-world delivery model,” she said.

After disclosure, study personnel will follow up with participants by phone within two to seven days to see how they are coping with the information. Additional follow-ups will occur at six weeks, six months, and 12 months. Researchers will administer a battery of psychological tests, including for anxiety and depression, as well as surveys adopted from REVEAL that assess attitudes and knowledge about genetic testing. The surveys will measure how well people remember the results of testing, as well as how satisfied they are with the process. The researchers also want to explore the effects of testing on family members, since a positive result implies that relatives may be carriers as well. “We need to think about these issues as we move forward to a time when more and more people may learn their genotype,” Langbaum said. She noted that so far, the people she has spoken to seem very interested in learning their results. “They want to know they are at increased risk before embarking on such a long trial,” she said.

Researchers will watch for cognitive effects of disclosure as well, including the  “stereotype threat” whereby a negative perception becomes a self-fulfilling prophecy. For example, a recent study of 144 cognitively normal older adults found that those who knew they carried an ApoE4 allele rated their own memory more poorly and performed worse on tests of verbal memory than ApoE4 carriers who did not know their genotype (see Lineweaver et al., 2013). In a separate follow-up study, API researchers will invite participants from the disclosure study to complete online cognitive assessments and answer questions about how they think they are doing mentally. For controls, the study will enroll some people who donated DNA but did not learn their genotype. Researchers will examine whether ApoE4 carriers who learned their genotype perform differently than those who did not, or have more concerns about cognition, and whether this effect varies with the number of copies of ApoE4.

“We want to make sure that genetic disclosure is done in the best way to try to minimize any negative impact,” Langbaum said.—Madolyn Bowman Rogers


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News Citations

  1. How Do You Communicate Alzheimer’s Risk in the Age of Prevention?
  2. Early ApoE4 Memory Effects, But Do You Really Want to Know?
  3. To Reveal or Not to Reveal? New Data on the Question
  4. Novartis to Partner with Banner Health on ApoE4 Prevention Trial

Webinar Citations

  1. Susceptibility Testing and Risk Assessment in Alzheimer Disease

Paper Citations

  1. . Telegenetics: a systematic review of telemedicine in genetics services. Genet Med. 2012 Sep;14(9):765-76. PubMed.
  2. . Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer. J Clin Oncol. 2014 Mar 1;32(7):618-26. Epub 2014 Jan 21 PubMed.
  3. . Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial. J Natl Cancer Inst. 2014 Dec;106(12) Print 2014 Dec PubMed.
  4. . Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014 Feb;171(2):201-8. PubMed.

External Citations

  1. Alzheimer’s Prevention Registry

Further Reading