Brain diseases such as Alzheimer’s disease are among those that patients fear most, next to only cancer.1 In addition to exacting a heavy toll on patients’ personal, social, and financial well-being, brain diseases often undermine patients’ very sense of personal identity. Although these devastating diseases are often diagnosed only after irreversible brain damage has occurred, increasingly advanced and accessible medical technologies have raised the prospect that they could be recognized at earlier and earlier stages. In recent years, some patients searching for answers about their health have used genetic testing to learn whether they are at heightened risk of developing Alzheimer’s or other potentially life-changing illnesses. Researchers have developed biological tests for brain diseases holding ever-greater predictive power, and each new discovery raises the hope among patients and clinicians alike that these diseases could one day be diagnosed and treated even before symptoms occur. Preclinical diagnosis, however, also raises unique ethical issues that must be resolved before the full benefits of these advances can be realized. These challenges must be met by multiple stakeholders across the health care system, including providers, policymakers, and patients and their family members. Considering the ethical implications of preclinical diagnosis may help society to use these emerging medical technologies to the benefit of all.
In this, Part 4 of this series, we discuss the ethical implications behind these topics based on presentations by Professor Karen Rommelfanger, Center for Ethics, Emory University School of Medicine, Atlanta, USA.
Ethics and the “pre”-patient
Ms. Parker, a healthy 61-year-old woman with a family history of early onset Alzheimer’s disease, desperately sought knowledge as to whether she, herself, was at a greater risk of developing dementia later in life. To this end, she requested and received the following news from a genetic counsellor following the submission of her saliva for DNA testing:
“Based on the results of your genetic testing, Ms. Parker, we have found that you are at greater risk for the development of Alzheimer’s disease. This does not mean that you will one day experience Alzheimer’s disease, only that you are at a greater risk based on your genetic testing results.”
What does Ms. Parker do with this information? At present, she is a healthy, active woman in her early sixties. What does she do now?
The unknown known
Ms. Parker’s hypothetical situation is quickly becoming the new norm in medicine. Although it cost nearly $3 billion USD to sequence the first human genome in 2003, whole-genome sequencing can now be accomplished in under two weeks for less than $1,000 USD.2 For an even lower price (currently $199 USD), direct-to-consumer genetic testing companies such as 23andMe will search an individual’s genome for genetic variants linked with a higher risk of developing 10 diseases, including late-onset Alzheimer’s disease and Parkinson’s disease.3 23andMe’s tests were approved by the U.S. Food and Drug Administration (FDA) in 2017, pushing consumer genetics firmly into the mainstream. But while the pace of technological change has accelerated, our understanding of the ethical issues raised by these advances has lagged behind. How should clinicians discuss the results of these tests with someone like Ms. Parker, and how should patients interpret information related to genetic health risks? Patients want to know. Clinicians want to know.
A major challenge for patients and clinicians alike is that a positive genetic testing result is not the same as a clinical diagnosis. As discussed in the first article in this series (“Identifying Prodromal and Preclinical Brain Diseases”), the risk of developing a neurological or psychiatric illness is shaped by the complex interaction between a person’s genetic profile and a range of environmental vulnerabilities. In other words, genetic risk is only one of many factors that influence whether a person will or will not develop a disease. For example, consider the apolipoprotein E (ApoE) E4 allele, which is known to increase the risk of developing Alzheimer’s disease and is detected by consumer genetics tests for the disorder. Although carrying the ApoE4 allele increases one’s risk of Alzheimer’s by several-fold (and carrying two copies of the allele increases the risk even more), many people with this risk variant will never develop the disease.4-5 Preclinical detection is therefore rarely a matter that is black and white (Figure 1).6
Figure 1. The clinical trajectory of Alzheimer’s disease
The line between preclinical and clinical disease states is poorly defined. MCI = mild cognitive impairment. Source: Figure adapted from Sperling et al. 2011.6
The grey areas of preclinical detection have given rise to a new kind of patient: the “pre”-patient. Pre-patients such as Ms. Parker run an increased risk of developing a disease that may or may not ever occur. The resulting ethical issues are numerous. What should pre-patients do with the knowledge that they could likely develop a life-changing illness, and how should this information affect their clinical management? Rapid advances in this area also have implications for privacy. Should a pre-patient’s health information, for example, be legally protected from disclosure to third parties, such as employers or health insurers? These ethical challenges and tentative solutions are explored below.
The right to know (and not to know)
Patients today are more empowered and engaged in their own health care than ever before. New technologies—such as online personal health records and wearable devices that collect health data in real time—have made health care more transparent for millions of people. For patients seeking even more information about their health, the answer for some has been to peer into the black box of their own genomes.
As noted by the cognitive scientist Steven Pinker, we think of our genetic makeup as a core part of who we are.7 For some patients, the decision to have one’s genome sequenced may be driven by curiosity or novelty. For others, especially those with a family history of neurodegenerative disease, the same decision may be highly personal. Twin and family studies show that genetic factors play a large role in Alzheimer’s disease, with its heritability estimated at 60 to 80 percent.8 For these patients, the discovery that one carries a copy (or two) of the ApoE4 allele may present an opportunity to plan for the future, such as by having children earlier in life or planning to retire at a younger age. People who know their genetic risk may also be motivated to make lifestyle changes that could reduce their risk for disease.9 Consider Sergey Brin, the Google co-founder and president of Alphabet, who discovered that he has a genetic mutation predisposing him to Parkinson’s disease.10 Brin took the news as an opportunity to reduce his risk through diet and exercise—and to support translational research focused on creating new disease-modifying therapies.
By contrast, some who have had their genomes sequenced, such as Pinker and James Watson, the co-discoverer of the structure of DNA, have specifically declined to learn their ApoE4 status.11 Many people understandably do not wish to know that they may be at high risk of developing a severe and ultimately debilitating illness, especially one for which there is currently no cure. Such a preference should be respected.12
For those patients who do choose to know their disease risk, researchers have developed prediction tools of ever-growing sophistication. One test combining more than two dozen susceptibility genes, each of which has only a very small effect in isolation, has shown greater promise in predicting the onset of Alzheimer’s in cognitively normal older adults than ApoE4 alone.13 Likewise, panels of novel blood-based biomarkers could be used to detect the disease years before cognitive decline occurs.14-15 Although it is too early to translate these biomarkers into clinical practice, it is likely that patient demand for accurate and timely diagnostic tools will only continue to increase.16
Whether patients want to live with the knowledge of their genetic risk for specific diseases or not, the broader health care system will need to adapt to the technological changes that have provided patients with a choice. In the U.S., clinical guidelines recommending against routine genetic testing for Alzheimer’s disease were published in 2011—before personal genomics had become an everyday experience and when preclinical diagnostic algorithms were not yet the focus of intense research attention.17 Even public attitudes toward genomic testing have changed in recent years. As Pinker observes, the genome has become democratized, and people have become accustomed to wielding greater control over their own health information.7 For those who do exercise their right to know, the key question is how genetic risk information should influence a pre-patient’s future treatment and management.
Avoiding undue harm
All medical interventions involve an assessment of risks and benefits, and the preclinical diagnosis of brain diseases raises ethical challenges that may have far-reaching consequences. Physicians must be prepared to discuss genetic test results that resist easy interpretation and may have limited utility for treatment. Patients who are given a preclinical diagnosis or learn that they are at high risk of developing dementia may feel depressed or stigmatized. The preclinical detection of brain disease also has implications for employment, health insurance availability, and practical activities such as driving that have yet to be adequately assessed by the medical community or the broader public. The path ahead is unclear, and all stakeholders must work together to ensure that advances in genomics and imaging continue to support human dignity.
Insights drawn from the field of cognitive psychology suggest that people are generally poor judges of probability and risk.18 In the setting of genetic susceptibility testing, one barrier is that genetic risk information—such as the significance of carrying the ApoE4 allele—may easily be misunderstood or misinterpreted.19 Even highly trained physicians struggle to understand and communicate the probabilistic nature of genetic tests.20 As a result, it is easy to imagine that frustration could occur if a patient brought her test results to a physician who was unprepared to interpret them, or if a doctor ordered genetic testing for a patient that was inappropriate or did not change recommendations for treatment. The breakthrough pace of scientific progress makes it all the more important that medical trainees receive better education in genomics.21
Many patients also struggle to interpret risk and complex health information. Given the cognitive biases we all share, patients who receive probabilistic information tend to reduce or simplify it to a binary outcome.19 Pre-patients who learn that they have a 50% lifetime risk of developing Alzheimer’s, for example, may mistakenly believe that they are either certain to develop the disease or will never do so. Other pre-patients may have difficulties retaining complex medical information. Some empirical evidence on how patients recall genetic risk information comes from the REVEAL study (Risk Evaluation and Education for Alzheimer’s Disease), a randomized controlled trial examining the psychosocial impact on patients who were disclosed their ApoE4 genotype. After one year, only 63% of the REVEAL study participants were able to recall their genotype, and less than half (48%) could recall their lifetime risk estimate.22 These findings emphasize that health care providers need to make risk information more memorable or “sticky” for their patients. In the REVEAL study, patient education techniques included the use of illustrations and other visual aids to explain how one’s disease risk changed across the lifespan.23 Although the specific tools may vary, it is clear that genetic test results must be shared with patients in a way that promotes their understanding.
As mentioned above, it is essential that patients know the limitations of their test results. The ApoE4 gene (or any other biomarker) is only one of many factors influencing disease risk. Conversely, some patients who have no known susceptibility factors will nevertheless develop the disease—about half of Alzheimer’s patients, for example, do not carry the ApoE4 allele.24 Given the inherent complexities of susceptibility testing, most experts recommend that patients meet with a genetic counsellor beforehand.17 After patients make an informed decision to undergo testing, genetic counsellors can help pre-patients understand what the results could mean for them and their loved ones.
Most people think of the brain—the location of all our emotions and memories—as integral to human identity. Pre-patients who learn that they are at elevated risk of developing a neurodegenerative disease will react in different ways: some may experience distress, while others may gain security from knowing their health status. Others may regret opening a Pandora’s box of genomic data that can never be closed again.25 Genetic susceptibility tests therefore raise concerns about their potential for psychological harm.
One study suggests that few pre-patients, in fact, experience lasting psychological consequences from receiving a positive test result. In the REVEAL study mentioned previously, 162 asymptomatic adults who had a parent with Alzheimer’s were assigned at random to two groups: those who were disclosed their ApoE4 genotype and those who were not.26 The participants who tested positive for ApoE4 showed levels of anxiety, depression, and test-related emotional distress that were no higher than in the nondisclosure group. Participants who were told that they were not ApoE4 carriers, conversely, showed less test-related distress than did the ApoE4-positive subgroup. These findings suggest that genomic testing for brain disease may not pose substantial psychological risks—at least in a select group receiving genetic counselling. The REVEAL study, however, did not address the social and financial consequences of testing or its long-term psychological effects.27 In addition, whether the REVEAL study’s findings can be generalized to the broader public remains unclear.
Another consideration is that preclinical diagnosis of Alzheimer’s or other brain diseases may invite stigma and discrimination. For some pre-patients, fear of cognitive decline may even become a self-fulfilling prophecy, leading to a pattern of underperformance known as the “stereotype threat.” This phenomenon is demonstrated by a recent study in which people who knew they carried the ApoE4 allele judged their memories more critically and performed worse on a memory test than ApoE4 carriers who did not know their genotype.28 Given these findings, providers should assure pre-patients that biomarker evidence of disease risk is used to help, not to label or stigmatize.
The preclinical diagnosis of brain diseases raises legal and policy implications that extend far beyond the doctor’s office. Some pre-patients may face discrimination from insurers and employers due to their health status.29 In some jurisdictions, a diagnosis of Alzheimer’s disease could affect one’s right to hold a driver’s license.30 Because patients’ preclinical health information carries a high potential for consequence, it is imperative to protect it against unauthorized disclosure to third parties.31
Preclinical diagnosis, finally, raises questions of cost-effectiveness in a time of limited health care resources.23 High patient demand for genetic susceptibility testing threatens to overwhelm memory clinics, potentially resulting in unneeded care while reducing access for patients with established illness.32 Under the ethical principle of distributive justice, society must ensure that scarce health care resources are prioritized to those who most need them, and that preventive services such as screening and counselling are readily available to those at greatest risk.
Although not answering all of the ethical questions raised by preclinical diagnosis of brain disease, Karlawish has proposed a three-step framework that may be useful to physicians and policymakers. These steps are to: (1) establish guidelines for researchers and clinicians to safely and effectively communicate the preclinical diagnosis to patients; (2) set up a process that translates this diagnosis into practice and policy; and (3) adapt laws, regulations, and professional practices to the diagnosis of preclinical disease.33 In other words, stakeholders will need to establish as both a scientific and normative matter who should undergo biomarker testing, what constitutes a preclinical disease state requiring treatment, and how to prepare for disease onset.
Medical advances have raised the hope that debilitating brain diseases could soon be identified and treated before patients show clinical symptoms. Our enthusiasm for the transformative potential of these new technologies, however, should be tempered by our knowledge of their ethical challenges. In the years ahead, it is likely that millions of people will undergo genetic or other biomarker testing that could raise more questions than they answer about their future health. Pre-patients who face an uncertain road forward will turn to health care providers and policymakers for clarity. Our challenge will be to translate the growing flood of biomarker data into a public health framework rooted in evidence-based prediction and prevention strategies. Most important of all, such a framework must be guided by the fundamental principles of clinical ethics—including the imperative to place patient needs and preferences at the front and centre.
Access the four-part series When “Patients” are not “Patients” (Yet)
We would like to thank Professor Rommelfanger for sharing her expertise on this topic and for her time in providing feedback to this article. Find out more about her work here: http://ethics.emory.edu/people/Faculty/Karen_Rommelfanger.html.