Part 1 of two.

With the growing use of biomarkers, researchers can now identify cognitively normal people who are at elevated risk for Alzheimer’s disease. This has enabled secondary prevention studies such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial. To participate in this type of study, however, people typically need to learn about their risk factors. It is not feasible to keep participants blinded on this point, as that would necessitate including many more people, ballooning the cost of these already-expensive undertakings, researchers said. Hence clinicians are now grappling with how best to disclose risk information to cognitively healthy people without causing undue despair. They also want to monitor how the information affects people’s psychological well-being and cognitive function in the long term.

At the Alzheimer's Association International Conference 2015, held last month in Washington, D.C., speakers detailed innovative ways in which the A4 trial and the Alzheimer’s Prevention Initiative’s ApoE4 trial are approaching the issue, the former revealing brain amyloid imaging results and the latter ApoE genotype (see Dec 2014 conference news). Researchers are drawing inspiration from the breast cancer field, where communicating genetic risk has become standard practice, noted Angela Bradbury of the University of Pennsylvania in Philadelphia, and from the AD REVEAL studies that disclosed ApoE status to participants. However, AD researchers face logistical barriers in scaling up these previous disclosure models to communicate risk to several thousand people within the setting of a large trial. To accomplish this, the API ApoE4 study will make extensive use of remote technologies such as the Internet, telephone, and videoconferencing (see Part 2 of this story). 

“We’re starting to think about providing risk information and empowering participants to make decisions based on this information,” Jessica Langbaum of Banner Alzheimer’s Institute in Phoenix told Alzforum. “I think in the coming years we’ll see more and more studies that disclose.”

Little data is yet available to determine how well these new protocols work, but preliminary results from small studies suggest that most people enrolled in trials handle knowing their risk well, speakers said. Surveys also reveal a growing desire for that knowledge, particularly if that qualifies the person for a treatment trial. Overall, the talks showcased a field moving toward an era of widespread risk disclosure.

At the same time, speakers acknowledged looming societal unknowns, such as whether knowledge of AD risk could lead to insurance or other types of discrimination. Federal law prohibits employers and health insurers from discriminating against people based on genotype, but this protection does not extend to amyloid-imaging results. Likewise, disability, life, and long-term-care insurers are not bound by the same federal protections (see Aug 6 conference newsJun 2008 news). Long-term care is particularly important, since many people at risk of AD purchase such coverage, speakers said, adding that this is fast becoming a pressing issue for legislators to resolve.

Laying the Groundwork for Disclosure Trials
Cancer researchers have forged this path already. Twenty years ago, after the identification of variants in the BRCA1 and BRCA2 genes that magnify the risk of breast cancer, clinicians struggled with the issue of how to tell women about their genetic status. “We were concerned about their ability to understand complex genetic information, and the potential for distress when facing tough decisions about prophylactic surgery,” Bradbury told Alzforum. Bradbury is an expert in the ethics of breast cancer risk disclosure.

In the classic genetic counseling model, people who may carry risk variants first meet with a counselor face-to-face to learn about the limitations of testing and give consent to the procedure. They return for a second meeting to hear the results. Genetic counselors assess their mood and anxiety, and follow up later by phone to see how they are coping with the information. Providers in the cancer field developed several strategies for communicating technical genetic information, including using visual aids and providing only a small amount of information at a time to avoid overwhelming people, Langbaum noted. Studies found that most women who went through the process did well over time and used the information to improve their health, Bradbury said (see, e.g., Lynch et al., 2006; Bosch et al., 2012; Borreani et al., 2014). 

Alzheimer’s raises different issues, however. Chief among these is that people with increased risk of the disease have no access to treatments that would slash their odds of getting sick. Many researchers worry that knowledge of brain amyloid or ApoE status would be deeply distressing to cognitively healthy, middle-aged people, perhaps lowering their quality of life or leading to rash decisions. Even so, surveys indicate that an increasing number of people want to know their AD risk.

At AAIC, Joshua Grill of the University of California, Irvine, presented a poster describing attitudes toward genetic testing among 80 participants in the Dominantly Inherited Alzheimer’s Network (DIAN). For these people, who may have inherited a familial AD gene, a positive test result means they are destined to develop the disease. Nonetheless, 55 percent wanted to know their genetic status. Among those who did not, almost three-quarters said they would change their mind if knowing their status gave them access to a clinical trial. All but one person said they would get testing and join such a trial if they were assured of getting active drugs during an open-label extension study (see Grill et al., 2015). “That is a big jump in interest from previous surveys,” Grill told the audience.

Anecdotal reports suggest that more people at risk for familial disease are choosing to get tested now than ever before. Many of these people recently shared their stories at a July 18 DIAN meeting in Washington, D.C. (see Aug 2015 conference news). 

Attitudes appear similar among people at risk for late-onset AD. Brian Ott of Brown University, Providence, Rhode Island, presented data from 158 participants in the Rhode Island Alzheimer’s Prevention Registry. In this cohort, three-quarters had at least one parent with AD, and half cared for someone with the disease. Only 15 percent already knew their own ApoE or amyloid-imaging results, but of those who did not, 80 percent said they wanted to find out. The most common reasons they cited were to participate in research and plan for their future. Likewise, a recent survey of 4,036 people enrolled in the Alzheimer’s Prevention Registry found that 89 percent of them wanted either genetic or biomarker testing, Langbaum noted. Ninety percent said they would seek a healthier lifestyle if test results were positive. Ominously, 12 percent reported they might consider suicide (see Caselli et al., 2014Caselli et al., 2015). 

This latter finding dovetails with experiences from oncology. Although most patients do well after finding out they have a genetic risk for breast cancer, there are also subgroups of people who find the information very distressing and will struggle, Bradbury said. As the Alzheimer’s field moves toward incorporating disclosure into trials, it will be important to identify these subgroups and develop protocols to minimize psychological risk for them, Bradbury noted. 

The Next Frontier: Disclosure of Amyloid Status
With the Food and Drug Administration’s approval in recent years of three amyloid imaging tracers, cognitively normal people now have the option to find out if they are accumulating amyloid deposits in their brain. Large prospective studies have linked brain amyloid to a greater risk of cognitive decline within a few years (see Dec 2014 conference news). The field is grappling with the issue of whether to tell cognitively normal adults their amyloid status, and if so, how and under what circumstances (see Feb 2012 conference news). 

In D.C., David Johnson of the University of Kansas, Lawrence, presented preliminary data that suggested many people can handle this information well. As part of the APEX exercise study at his institution, 85 cognitively normal participants went through a counseling protocol similar to that used in genetics, and learned their brain amyloid status. In this cohort, 25 people had positive amyloid scans. Researchers followed up with participants six weeks and six months after disclosure. Six weeks after testing, clinical measures of anxiety and depression stayed stable, and low, in all groups; however, people with a positive scan did report feeling more upset, sad, anxious, or worried. In nearly all cases, participants listed these feelings as being “very rare” or “infrequent,” and the frequency declined to nearly baseline measures by six months. The researchers saw no change in memory performance, or in how participants rated their own memory. People with positive scans did report a greater intent to exercise than those with negative results, however.

In a similar vein, Michael Pontecorvo of Avid Radiopharmaceuticals, Philadelphia, updated the audience on a trial that examines the health outcomes of amyloid imaging (see Aug 2015 conference news). Patients with memory complaints who were randomized to the disclosure arm of the study did not demonstrate any significant psychological distress upon learning the news, he said. Researchers saw no changes in measures of anxiety, depression, or psychotropic drug use.

More data may soon be available. The A4 trial enrolls cognitively normal people between 65 and 85 who have a positive amyloid scan. With an enrollment goal of 1,150, trial investigators will have to inform large numbers of people of their amyloid status. Researchers formed a group of six amyloid imaging experts and six genetic-testing experts to develop a protocol for this (see Harkins et al., 2015). Jason Karlawish of UPenn, who leads the A4 disclosure study, said that this group incorporated lessons from REVEAL in this work.

As in genetic-disclosure models, participants first meet with A4 personnel for an educational session. There, they learn about the science behind amyloid imaging and what a positive or negative result means in terms of risk. For A4, these meetings will be face-to-face. People who decide to proceed sign a consent form. Then the investigator assesses each participant’s motivation for getting the scan, as well as their understanding of the process, and administers standard psychological tests for anxiety and depression. If no concerns surface, they schedule the scan. Some days after the scan, the participant returns for a face-to-face disclosure session, accompanied by a friend or family member if desired. The investigator again assesses the participant’s mood and willingness to receive the results, then discloses the findings using scripted language. Study personnel follow up by phone within three days to see how participants are coping. While no data from the A4 study is yet available, about 200 people have now gone through the procedure, and the process appears to be working well, Jeffrey Burns of the University of Kansas, Kansas City, told the audience in D.C.

A4 researchers also look at the long-term impact of disclosure. The companion Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) will track people in the A4 study from just after disclosure to nine to 12 months later, and compare them to people in the adjunct observational LEARN study who have discovered that they do not have brain amyloid. Participants will complete measures of mood and cognition, and estimate how much time they think they have left to live. “The goal is to understand how people incorporate information about amyloid status into their sense of self,” Karlawish told Alzforum. Researchers will also investigate how the knowledge affects participants’ social relationships, and whether they are subject to stigma (see Sep 2012 news). 

Overall, these studies are paving the way toward a future when physicians might routinely disclose brain amyloid status as part of clinical care, Karlawish noted. Thus, researchers need to find the best ways for physicians to communicate and interpret these results for patients. But Karlawish believes the issue is bigger than that. “We also need to make sure that learning this information has value to patients,” he said. Other speakers noted that once an effective Alzheimer’s treatment becomes available, people may demand to know their amyloid status. However, Karlawish pointed out that even the existence of treatment options might not mitigate the stress of such knowledge. Rather, a potential treatment would introduce uncertain risk-benefit calculations to the equation, such as how safe the treatment is and how much it delays disease, without changing the fundamental reality of dealing with impending Alzheimer’s disease. “There may be an existential burden to learning that one’s brain is at risk for, or in the process of, failing,” Karlawish suggested.—Madolyn Bowman Rogers


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News Citations

  1. From Shared CAP, Secondary Prevention Trials Are Off and Running
  2. Testing a New Model for Disclosure of ApoE4 Status
  3. At DIAN Family Meeting, Funding News Caps Talk of Inadequate Services
  4. GINA No Genie for Alzheimer Disease Patients and Relatives
  5. 100 DIAN Family Members Gather for Their First International Meeting
  6. Large Studies Agree: Brain Amyloid Accelerates Cognitive Decline
  7. Miami: Scan and Tell? Amyloid Imaging Confronts Disclosure Dilemma
  8. Amyloid Scans in the Clinic: Seeing Is Believing?
  9. World Alzheimer Report Says Stigma an Impediment to Care

Paper Citations

  1. . Patient responses to the disclosure of BRCA mutation tests in hereditary breast-ovarian cancer families. Cancer Genet Cytogenet. 2006 Mar;165(2):91-7. PubMed.
  2. . What factors may influence psychological well being at three months and one year post BRCA genetic result disclosure?. Breast. 2012 Dec;21(6):755-60. Epub 2012 Feb 28 PubMed.
  3. . The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers. Clin Genet. 2014 Jan;85(1):7-15. Epub 2013 Nov 5 PubMed.
  4. . A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):50. Epub 2015 Jul 22 PubMed.
  5. . Public perceptions of presymptomatic testing for Alzheimer disease. Mayo Clin Proc. 2014 Oct;89(10):1389-96. Epub 2014 Aug 26 PubMed.
  6. . Predictive testing for Alzheimer's disease: suicidal ideation in healthy participants. Alzheimer Dis Assoc Disord. 2015 Jul-Sep;29(3):252-4. PubMed.
  7. . Development of a process to disclose amyloid imaging results to cognitively normal older adult research participants. Alzheimers Res Ther. 2015;7(1):26. Epub 2015 May 12 PubMed.

External Citations

  1. Alzheimer’s Prevention Registry
  2. APEX 
  3. A4 trial
  4. LEARN study

Further Reading