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Genetic testing for risk of Alzheimer’s disease: benefit or burden? “Moving APOE testing from a controlled research setting to a widely available consumer service raises numerous questions about potential social harms and unintended consequences.” J Scott Roberts* Genetic testing for the risk of Alzheimer’s disease (AD) using APOE genotyping has been discouraged owing to its limited predictive value, a lack of AD treatment options and concerns about psychosocial harms (e.g., psychological distress, genetic discrimination). However, extant studies on the psychological and behavioral impact of APOE testing on asymptomatic individuals suggest that such harms are rare and modest, and may be outweighed by various benefits that at-risk individuals report as responses to test results (e.g., informing advanced planning and health behavior change). This editorial suggests reasons why the medical community may wish to reconsider a rigid stance against the disclosure of APOE information to interested individuals, and describes the opportunities and challenges involved in expanding access to this type of testing. The proper uses of genetic testing for risk of AD have been debated since the mid-1990s, when it was discovered that the e4 allele of the APOE gene confers a significantly elevated risk of disease. Several expert consensus statements, at the time, cautioned against the clinical
use of APOE testing with asymptomatic individuals, citing the test’s limited predictive value (the e4 allele is neither necessary nor sufficient to cause AD), a lack of proven treatment and prevention options and concerns about potential psychological and social harms posed by test results [1] . An updated consensus statement from the American College of Medical Genetics and the National Society of Genetic Counselors continued to advise against the use of APOE testing for clinical purposes, although it allowed that in certain cases, “testing may be considered at the clinician’s discretion” [2] . Although these policy statements have sensible rationales and are provided with patient welfare in mind, I would argue that there are numerous reasons why we may want to reconsider a highly rigid stance against the disclosure of APOE genotype information by a qualified provider. First, the supposed psychological harms of risk information alluded to in initial policy statements have not materialized, at least when disclosure of APOE test results is conducted in a controlled research setting by expert clinicians. We have examined
“...there are numerous reasons
why we may want to reconsider a highly rigid stance against the disclosure of APOE genotype information by a qualified provider.”
*Department of Health Behavior & Health Education, University of Michigan School of Public Health, 109 S. Observatory, Ann Arbor, MI 48109, USA Tel.: +1 734 936 9854; Fax: +1 734 763 7379;
[email protected]
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Editorial Roberts this issue in a series of NIH-funded clinical trials known as the REVEAL Study, where several hundred unaffected first-degree relatives of people with AD have been provided with estimates of their lifetime risk of AD based on their APOE genotype, age, gender and family history [3] . Disclosure of APOE genotype (typically delivered by a genetic counselor) and associated risk of AD have not generally resulted in significant depression or anxiety symptoms, and relief from an e4‑negative result has been much more commonplace than distress from an e4‑positive result [4] . These data are consistent with findings from the broader genetic testing literature, where disclosure of genetic risk, even for severe, incurable diseases, such as Huntington’s disease, has not typically engendered significant psychiatric difficulties [5] . Withholding of potentially threatening information is a time-honored tradition in medicine (e.g., diagnoses of conditions, such as AD and cancer, were once routinely kept from patients). But we should be mindful as to whether such decisions are truly in the best interest of the patient and are not merely reflective of unverified assumptions or discomfort with a difficult topic. The psychological literature on affective forecasting would suggest that our judgments in this area are systematically biased. For example, cognitive psychologists have long known about the impact bias – a seemingly universal tendency to overestimate the intensity and durability of our (and others’) psychological reactions to future events [6] . This bias has been demonstrated in various medical contexts, where projected negative responses to stressful medical situations have been significantly greater than those that actually occurred [7] . Decisions to restrict access to APOE testing are not just made because of feared catastrophic reactions, but also on the basis of clinical utility; because the test’s results do not inform medical care options, it is not offered. But another reason to consider disclosure of APOE genotype information is because many at-risk individuals are interested in such testing and have found its results to have personal value. Various studies of motivations for pursuing genetic testing for AD have suggested that perceived benefits of testing greatly outweigh the perceived limitations and risks, with information viewed as helpful to inform advance planning, encourage monitoring of developments in the field and assist coping with uncertain risk status [8,9] . Hardly anyone who has undergone APOE testing in existing
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studies has reported regrets about the decision, and the test process has seemed to prompt some positive health behavior and insurance changes [10,11] . Interested parties have reported, in national surveys and clinical studies, that they would be willing to pay significant amounts for test information, with one national survey finding that respondents were willing to pay a mean of US$193, even for an AD test of modest predictive value (i.e., a positive test would indicate 25% lifetime risk as compared with the general population risk of 10%) [12,13] . Of course, one must be wary of advocating a blind trust in a consumerist view of medical testing (10 million APOE fans cannot be wrong). Furthermore, in an age of constrained healthcare resources, personal utility alone should not be a sufficient criterion for insurance coverage of a limited test such as APOE genotyping. But I do believe we may need to take more seriously the notion that disease risk information may be of interest to patients and family members for a wide variety of ‘nonmedical’ reasons, many of which should not be dismissed out of hand as irrelevant to the mission of clinical care. Furthermore, the concept of personal utility of health risk information is likely to become more prominent given the increasing availability of personal genomic information through consumer services and other sources. Indeed, proponents of consumer genetics (as well as more libertarian-minded genomic researchers) have made the argument that access to information, such as APOE status – and about one’s genome in general – is a matter of personal autonomy, with current restrictions unduly paternalistic [14] . Some companies now offer APOE testing direct-to-consumer, with test results and education provided online, and no in-person genetic counseling required [101,102] . It is highly uncertain whether some of the earlier stated conclusions about the benefits and harms of testing would generalize to this delivery mode. What we know about responses to APOE test information comes from studies where generally well-educated participants screened for cognitive and psychiatric impairments have specifically sought out this information, and where pre- and post-test education and support have been delivered in person, typically by a certified genetic counselor. Moving APOE testing from a controlled research setting to a widely available consumer service raises numerous questions about potential social harms and
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Genetic testing for risk of Alzheimer’s disease: benefit or burden? unintended consequences. For example, how would long-term care insurers react to potential adverse selection based on APOE information (current genetic discrimination laws only apply to employers and health insurers)? Would increased awareness of AD risk via gene testing lead to increased marketing of unproven ‘antiaging’ supplements and nutraceuticals? If APOE information is delivered as just one among many pieces of genetic risk information across numerous diseases, does this heighten the possibility of patient misunderstanding and/or unexpected distressing results? To answer such questions, we need to move beyond speculation to empirical studies, which may necessitate the careful development of research collaborations between independent academic investigators and personal genomics companies [15] . Although the future benefits and burdens of genetic testing for AD are unknown, it does appear likely that this will continue to be a dynamic topic at the research, practice and policy levels. For example, studies investigating APOE as a pharmacogenomic marker are underway, where test results could theoretically inform decisions of prescribing physicians [16] . We continue to learn more about gene–environment interactions involving APOE; a recent study suggested that a more sedentary lifestyle was associated with higher cerebral amyloid deposition for e4 carriers but not noncarriers [17] . As new scientific findings accumulate and the AD treatment landscape evolves, the utility of APOE information could be transformed. For example, we are now seeing a move in AD treatment trials toward secondary prevention trials with asymptomatic samples classified as ‘at risk’ by virtue of a range of potential biomarkers [18] . APOE status could therefore help inform the risk/benefit calculation involved in one’s decision to enter such a clinical trial, or even to pursue a putative future
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Post SG, Whitehouse PJ, Binstock RH et al. The clinical introduction of genetic testing for Alzheimer disease. An ethical perspective. JAMA 277(10), 832–836 (1997). Goldman JS, Hahn SE, Catania JW et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and
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treatment with significant financial costs or side effects. In addition, what we learn from the experience of developing and communicating APOEbased risk estimates for AD may have implications for the disclosure of other biomarkers. One population of interest in the aforementioned secondary prevention trials is cognitively normal individuals with amyloid-positive neuroimaging results; informed consent for clinical research may necessitate the disclosure of amyloid status and its implications for development of clinically expressed AD. Thus, while the risk information yielded by APOE and other AD biomarkers is unclear, one thing seems certain: this topic will continue to generate debate and controversy in the years ahead. Financial & competing interests disclosure JS Roberts’ work is supported by the National Human Genome Research Institute grants R01-HG02213 (Risk Evaluation and Education for Alzheimer’s Disease) and R01-HG05092 (Impact of Personal Genomics). He is joint principal investigator of a NIH-funded grant (R01-HG05092) designed to evaluate consumer responses to personal genomics services offered by the companies 23andMe (CA, USA) and Pathway Genomics (CA, USA). The companies are collaborators in the implementation of study surveys, but analyses and interpretation of data will be independent. The author recently served on a Bioethics Advisory Panel convened by Eli Lilly and Company (IN, USA) to consider ethical issues involved in the use of its Florbetapir F18 agent. Florbetapir F18 injection is a molecular PET-imaging agent under investigation for the detection of b‑amyloid plaque in the brains of living patients with Alzheimer’s disease. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
the National Society of Genetic Counselors. Genet. Med. 13(8), 597–605 (2011).
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Editorial
Roberts JS, Christensen KD, Green RC. Using Alzheimer’s disease as a model for genetic risk disclosure: implications for personal genomics. Clin. Genet. 80(5), 407–414 (2011). Green RC, Roberts JS, Cupples LA et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N. Engl. J. Med. 361(3), 245–254 (2009).
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Neumann PJ, Hammitt JK, Mueller C et al. Public attitudes about genetic testing for Alzheimer’s disease. Health Aff. 20(5), 252–264 (2001). Roberts JS, Larusse SA, Katzen H et al. Reasons for seeking genetic susceptibility testing among first-degree relatives of people with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 17(2), 86–93 (2003). Chao S, Roberts JS, Marteau TM, Silliman R, Cupples LA, Green RC. Health behavior changes after genetic risk assessment for Alzheimer disease: the REVEAL Study. Alzheimer Dis. Assoc. Disord. 22(1), 94–97 (2008). Zick CD, Mathews CJ, Roberts JS, Cook-Deegan R, Pokorski RJ, Green RC. Genetic testing for Alzheimer’s disease and its impact on insurance purchasing behavior. Health Aff. 24(2), 483–490 (2005).
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spine loss caused by apolipoprotein E4 in primary cortical neurons. Proc. Natl Acad. Sci. USA 105(4), 1343–1346 (2008). 17
Head D, Bugg JM, Goate AM et al. Exercise engagement as a moderator of the effects of APOE genotype on amyloid deposition. Arch. Neurol. doi:10.1001/archneurol.2011.845 (2012) (Epub ahead of print).
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Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. Sci. Transl. Med. 3(111), 111–133 (2011).
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Green RC. Willingness to pay for genetic testing for Alzheimer’s disease: a measure of personal utility. Genet. Test. Mol. Biomarkers 15(12), 871–875 (2011). 14
In need of counseling? Nat. Biotechnol. 26(7), 716 (2008).
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Lehmann LS, Kaufman DJ, Sharp RR et al. Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing. Genet. Med. 14(2), 268–273 (2012).
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