In the era of secondary prevention trials for Alzheimer’s disease, knowledge is power. It also may be unavoidable. As large international study cohorts and clinical trials seek to enroll participants in the earliest stages, they must rely on biomarkers—such as amyloid accumulation in the brain or possession of the ApoE4 allele—rather than outward cognitive symptoms. This means that inviting someone to join such a trial equates to disclosing their AD risk status to them. At a session dedicated to this topic at the Alzheimer’s Association International Conference, held July 22-28 in Toronto, researchers grappled with developing ethical and efficient procedures to break this news to participants. They also presented emerging findings on the psychological, cognitive, and social impacts of doing so. So far, results indicate that most people use the information positively—they may exercise more, eat healthier, or make plans for their future care. Still, others may contemplate ending their lives.

“Understanding how people react to these test results is as important as understanding their response to a drug,” said Jason Karlawish of the University of Pennsylvania in Philadelphia. This still will be true once a disease-modifying therapy hits the market. “The future practice will be ‘get a test, get a drug,’ and we need to understand the combined impact of both of those interventions,” he said.

Investigators have a responsibility to take great care how, when, and to whom they disclose biomarker or genotype information, said Krista Tromp of Erasmus Medical Center in Rotterdam, the Netherlands. Tromp and colleagues are working to create ethical methods of disclosure in the European Prevention of Alzheimer’s Disease (EPAD) consortium. “On our path to a cure, we must make sure to protect the people who are helping us get there—the study participants,” Tromp said.

The AAIC session provided updates on disclosure issues discussed at last year’s meeting (see Aug 2015 conference news). 

Previous studies have suggested that among AD research cohorts, a majority of people want to know their genetic and/or biomarker status, and that they suffer no major psychological damage after they are told (see Ott et al., 2016; Lim et al., 2016Jul 2009 news). However, Tromp noted that these studies were largely conducted on people with a family history of AD, who were familiar with the disease and less surprised if they tested positive for AD biomarkers. With the massive recruitment of thousands of potential participants into AD prevention trials that is starting now and will only grow in the next few years, Tromp said researchers will need to consider how people who are less versed in the language of AD may react.

How might people respond differently to learning they carry an ApoE4 allele compared to testing positive for amyloid? While the evidence is not there yet, Tromp speculated that more people may be spurred to make positive lifestyle by learning they have amyloid accumulation than by learning they have an ApoE4 genotype. “Amyloid accumulation is an ongoing biological process—something is really happening. ApoE4 genotype is just a status,” she told Alzforum. “People might feel they can act more on a biological process.”

If disclosing AD risk status to cognitively normal people is ethically tricky, sharing biomarker information with people who have mild cognitive impairment has its own challenges. In a recent study, Jennifer Lingler of the University of Pittsburgh and colleagues developed a procedure for disclosing amyloid scan results to people with MCI along with their caregivers. They found that clear explanations of the complex data were key, and that research participants expressed a desire to see their scans and receive follow-up calls to answer emerging questions (see Lingler et al., 2016). Lingler said that upon learning of a positive amyloid scan, many participants may express relief that there is an underlying explanation for their symptoms. Compared with cognitively normal people, those with MCI may feel greater urgency to arrange for the future, and the scans might help them to do that, Lingler told Alzforum.

Generation GeneMatch
At AAIC, Jessica Langbaum of Banner Alzheimer’s Institute in Phoenix outlined the disclosure procedures underway in the Alzheimer’s Prevention Initiative’s (API) Generation Study. This trial aims to enroll approximately 1,300 people who carry two copies of the ApoE4 allele to test an Aβ vaccine and a BACE inhibitor, both by Novartis.

One source for participants in the Generation Study is GeneMatch, a program run by the Alzheimer’s Prevention Registry. People interested in participating in AD research sign up for GeneMatch online, and then use a mail-in cheek swab kit to get tested for their ApoE genotype. Since its launch in November of last year (see Dec 2015 news), more than 7,000 people have joined GeneMatch, of whom around 5 percent carry two copies of the ApoE4 allele, Langbaum said. Importantly, however, they will only learn their ApoE genotype if and when they are invited to join a clinical study and expressly agree to disclosure. While Generation is currently the only trial recruiting participants from GeneMatch, Langbaum said other trial sponsors are planning to tap this resource as well. Beyond AD, researchers planning gene-based trials in frontotemporal dementias are watching GeneMatch closely as it gathers early experience with this approach.

To avoid a situation where simply being invited to the trial signals de facto disclosure, the Generation Study has developed a statistical algorithm to invite a mix of ApoE4 homozygotes, heterozygotes, and non-carriers from GeneMatch to undergo prescreening for the trial. After pre-test counseling and a psychological assessment, willing and qualified participants are informed of their ApoE4 genotype. Those who carry two copies then receive an invitation to the treatment portion of the trial. Langbaum said the researchers developed this two-stage system to shield people from learning of their high-risk genotype unless they are also given the opportunity join the trial, and also to allow scientists the opportunity to prescreen people for signs of depression or anxiety that might make disclosure hazardous. The set-up also affords the researchers a chance to study the effects of disclosure not only on ApoE4 homozygotes, but also on heterozygotes and non-carriers.

As of now, people invited for prescreening in the Generation Study undergo pre-disclosure counseling and disclosure in one of three ways, depending on the resources at each study site. At sites that have a genetic counselor on staff, participants discuss one-on-one what a positive or negative test result could mean. The counselor emphasizes that there are no guarantees—a positive result does not mean a person will develop AD for sure, just as a negative one doesn’t rule out the disease. Participants then receive their genotype information. However, a majority of sites have no genetic counselor. At those centers, this same information is given on site, with a phone call from Penn Telegenetic Services, a genetic counseling service at the University of Pennsylvania that cut its teeth disclosing genetic information related to cancer risk.

A third option—remote video conferencing conducted on-site—is being tested as part of a trial called CONNECT 4 APOE. Headed by Angela Bradbury at UPenn, CONNECT 4 APOE will compare how satisfied participants are with phone versus video conferencing. This, too, came out of the more established field of genetic disclosure of cancer risk. The researchers hope to enroll 3,000 participants into CONNECT 4 APOE as an investigator-initiated sub-study conducted in parallel with the Generation Study. So far 12 sites are participating in CONNECT 4 APOE, with others coming on board. Regardless of their ApoE genotype, all participants in the Generation Study will be monitored for a year following disclosure to assess the psychological, lifestyle, and social impact of learning this information.

So far, 28 people have been invited to the Generation Study through GeneMatch, 14 of whom accepted and are in various stages of screening. To date, those who have learned their ApoE results have reacted well to receiving this information, Langbaum said at AAIC.

Making sure to get disclosure procedures right in the context of a trial is really just a practice run for the future, when a disease-modifying treatment becomes available, said Pierre Tariot of Banner, who co-leads the Generation Study. “If a treatment works, implications are that every adult in the world will want to know their genotype, and we need to know how to do that,” Tariot said.

How is A4 Handling the Hot Potato?
The A4 trial, which aims to enroll 1,000 people with positive amyloid scans, is studying a face-to-face disclosure method developed by Karlawish and colleagues (see Harkins et al., 2015). In that trial, participants meet with clinicians prior to the scan to learn what the results may mean and to undergo psychological screening. They then take home an extensive brochure describing the basic science of amyloid and AD. After signing a consent form, they return to receive the scan and ultimately, its results.

At AAIC, Karlawish updated researchers on the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES)-I, which is embedded within A4. The researchers are conducting two detailed interviews following the disclosure of scan results—one after four to six weeks, another after 12 months—on 50 participants with elevated amyloid and 30 people without elevated amyloid. So far, the researchers have finished both interviews for people with elevated amyloid, and the initial one for people with normal amyloid. The researchers asked participants to describe how the test results affected their lives, including how they changed their perception of how much time they have left, their own cognition, and their social and work relationships.

“Essentially, the use of biomarkers such as amyloid imaging has created a new disease state—one based on underlying pathophysiology rather than clinical symptoms,” Karlawish said. How people respond to existing in that new state, or being excluded from it, is the question studies such as SOKRATES-I seek to answer. Karlawish added that some people’s lives are so strongly based on their perception of their own cognitive strength that they may interpret emerging memory problems, or even just a positive amyloid scan, as threatening the core of their existence, despite their uncertain prognosis. For others, these early markers merely represent the beginning of a long journey with the disease.

Beyond SOKRATES-I, Karlawish and colleagues are conducting SOKRATES-II, which addresses similar questions for ApoE genotype disclosure in the Generation Study, and REVEAL-Scan, which will assess the cognitive effects of learning one’s amyloid status, much as the original REVEAL study had investigated ApoE genotype. Some researchers are concerned that learning of a positive amyloid status could affect a person’s cognition or perception of it, which in turn could alter trial results.

Disclosure in Countries Other than United States
For international studies, the disclosure field is further complicated by differing policies and cultures among participating countries. The European Prevention of Alzheimer’s Disease (EPAD) consortium is an example. Still in its recruitment phase, EPAD will serve as a source for participants in AD clinical trials, the earliest phases of which it will conduct itself.

The consortium recruits its participants from so-called “parent cohorts,” which are ongoing or completed regional and national studies on aged populations. Once invited by the investigator of their respective parent cohort to join the EPAD longitudinal cohort study (see Aug 2016 conference news), potential participants must agree to one day have their amyloid status disclosed to them. This sequence differs from the GeneMatch/Generation Study procedure, in which participants only agree to disclosure after they have been invited to a specific trial. After a potential EPAD participant has undergone prescreening and agreed to disclosure in the future, researchers measure CSF biomarkers, determine ApoE genotype, and administer cognitive tests. A subset of EPAD participants also undergo amyloid PET scans. With all this information in hand, EPAD trial sponsors can then invite specific participants who meet the risk profile they are looking for into the EPAD trial platform and randomize them to a specific trial arm. In essence, this means invitation to a trial will alert a potential participant of his or her risk status. That is why research participants in EPAD need to agree to learn their risk status at the start of their EPAD journey, Tromp said. Participants not invited to trials stay in the EPAD longitudinal cohort study tracking biomarkers and cognition; they can learn about their AD risk markers upon request.

“There will not be default disclosure of amyloid status just by entering the EPAD cohort; it only happens when a person is invited to a trial,” said Pieter-Jelle Visser of Maastricht University in the Netherlands, who coordinates recruitment of EPAD’s registry. “But if participants request this information, they have the right to know.”

While EPAD distributes educational materials on AD biomarkers to its participating centers across Europe, the precise methods for disclosure can vary between countries. Each has its own ethics review board. Tromp and colleagues are therefore also investigating the views on risk disclosure methods of ethics review boards.  Tromp said that EPAD is working to honor these country-specific practices while maintaining as much consistency as possible in the disclosure process.

EPAD is also running the Approaches to Communication of Alzheimer’s Disease Risk study. ACAR comprises nine focus groups in Barcelona, Spain, and London. Researchers in each of these groups are assessing people’s attitudes about learning their risk for AD, either in terms of biomarker status, lifestyle factors, or genotype, as well as their expectations of the disclosure process. At AAIC, Tromp presented preliminary findings of the study, which is led by Richard Milne of the University of Cambridge in England. So far, the researchers have learned that most people do want to know their AD risk status, but that their willingness decreases when they learn about the uncertainty associated with current information. People also want advice on how to improve their odds of avoiding AD.

Drawing the Line
While researchers are striving to put disclosure schemes in place for the upcoming clinical trials, what about everyday patients who see their doctor with memory complaints? Do they also have the “right to know” their amyloid status? Not unless there is a bona fide medical reason, according to Brian Ott of Brown University in Providence, Rhode Island. Ott told Alzforum that in a survey he conducted on people in the Rhode Island Alzheimer Prevention Registry, 80 percent of participants indicated they would like to know their amyloid status and/or ApoE genotype (see Ott et al., 2016). 

However, Ott pointed out that ordering these tests outside of a research setting—particularly for cognitively normal people—is a risky business. For one, the meaning of the results is not straightforward. People may live dementia-free for a decade or more after becoming amyloid-positive, and some ApoE4 carriers never develop AD. More worrisome, about 12 percent of people in Ott’s survey said they would contemplate ending their lives if given this information, despite the uncertain prognosis it would convey. Most of the people in Ott’s study wanted to learn their status for the purpose of participating in research. Attitudes about knowing one’s biomarker status may be different outside of research settings. But even in carefully managed prevention trials, occasionally people have had to be excluded because they expressed the possibility of suicidal thoughts if they were to learn of a positive amyloid scan, Karlawish told Alzforum.

John Morris of Washington University in St. Louis agreed that conducting amyloid PET scans or measuring CSF biomarkers in cognitively normal people in routine clinical settings is a ways off. “We just don’t know enough about what the results of biomarker tests portend, especially for people without memory problems,” he told Alzforum. Routine biomarker use could increase if results from the IDEAS study, which is measuring health and lifestyle outcomes of learning amyloid status in people who have clinical symptoms, indicate that gaining this knowledge leads to clinical benefits for recipients (see Apr 2016 news). This data would give health insurance providers a financial incentive to cover the scans for people with cognitive impairment and an otherwise uncertain diagnosis.

Karlawish added that presently, ordering a scan in the clinic in the absence of symptoms would be based on observational studies. This is shaky ground, he told Alzforum. Clinicians don’t do this now because they lack proof that amyloid scans predict disease, or that lifestyle interventions prevent disease. “Writing prescriptions based on observational data would be sloppy medicine, at best,” Karlawish said.

Of course, if an amyloid-targeted therapy is approved, clinicians will likely face an onslaught of people ready to head into the scanner.—Jessica Shugart


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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. GeneMatch Registry Recruits Subjects for Prevention Trials
  4. Coming to a Center Near You: GAP and EPAD to Revamp Alzheimer’s Trials
  5. Access: How to Bring People in ‘From the Wild’?
  6. $100M IDEAS: CMS Blesses Study to Evaluate Amyloid Scans in Clinical Practice

Paper Citations

  1. . A Survey of Knowledge and Views Concerning Genetic and Amyloid PET Status Disclosure. Alzheimers Dement (N Y). 2016 Jan 1;2(1):23-29. PubMed.
  2. . Disclosure of positron emission tomography amyloid imaging results: A preliminary study of safety and tolerability. Alzheimers Dement. 2016 Apr;12(4):454-8. Epub 2015 Dec 30 PubMed.
  3. . Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment. J Alzheimers Dis. 2016 Mar 8;52(1):17-24. PubMed.
  4. . 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.

Other Citations

  1. Aβ vaccine

External Citations

  1. GeneMatch
  2. Rhode Island Alzheimer Prevention Registry

Further Reading