A Case of Inappropriate Apolipoprotein E Testing in Alzheimer’s Disease Due to Lack of an Informed Consent Discussion

Abstract

Background/Objective:

Apolipoprotein E (APOE) genetic testing is used to assist in the diagnosis of Alzheimer’s Disease (AD). Whenever genetic testing is performed, an informed consent process should occur.

Methods:

In this case, a patient with memory loss presented to the neurologist. The neurologist ordered a lumbar puncture (LP). The LP was performed by a neuroradiologist who also ordered APOE genetic testing. The patient received no genetic counseling, nor was an informed consent document offered.

Results:

After the testing was completed, the neurologist faced an ethical dilemma. His solution was to offer the genetic testing to the patient in order to have an informed consent process. It was clear that the patient and her adult children did not want the genetic testing and that they would have been burdened with the results. The neurologist opted not to disclose the results.

Conclusion:

Genetic counseling and a signed informed consent document are required prior to any genetic testing. In this case, neither occurred and it led to an ethical dilemma that was ultimately resolved by the neurologist. As the population ages and AD becomes more prevalent, there is a need to expand the workforce of genetic counselors and educate physicians who commonly treat AD about genetic testing.

Introduction

Twenty years ago, the apolipoprotein E (APOE) ∊4 allele was found to confer susceptibility to late-onset Alzheimer’s disease (AD) in caucasians. ¹ This association was extended to noncaucasian populations, and the APOE-associated risk of AD was demonstrated to vary with age and sex. ² Although the presence of the ∊4 allele in a person with dementia increases the probability of AD, this finding is not “diagnostic” of the disease because more than one-half of ∊4 carriers surviving to age 80 years do not develop AD. ^2,3 Thus, APOE ∊4 is best viewed as a genetic risk factor for AD rather than a genetic marker of the disease ⁴ because the risk of developing AD for individuals with at least 1 ∊4 allele by age 80 years is estimated to be 29% compared to 9% for individuals lacking ∊4. ⁵

Among caucasians, the odds of developing AD are 2 to 3 times higher for ∊4 heterozygotes and 12 to 14 times higher for ∊4 homozygotes compared to persons who are APOE 3/3, the most common genotype. ² However, these risks are dependent on age and gender and are lower in some ethnic groups including African Americans, Indians, and Israeli Arabs. ^{2,6 –9} Further, the APOE risk appears to be attenuated by adequate control of hypertension. ¹⁰ The 2/3 genotype is associated with an approximately 40% decreased risk of AD compared to 3/3 genotype, ² and the 2/4 genotype has a similar risk as those with 3/3 genotype. ^2,11

Consensus exists among members of the scientific community that the value of APOE genotyping as a predictive test for AD in asymptomatic individuals is currently limited, with the weight of professional opinion against offering the test as part of a routine medical examination. ¹² Physicians may order APOE genetic testing in symptomatic patients in order to assist in the clinical diagnosis of AD. For some clinicians, APOE genetic testing is considered a supportive adjunct to the clinical diagnosis of AD. Alternatively, some clinicians believe that APOE genetic testing should be offered to patients as a matter of respect for the informed choice of the patient and family. ¹³

Although the value of APOE testing is generally viewed as limited, testing can have efficacy in some circumstances. Early diagnosis of symptomatic AD may be beneficial because some treatment options are most effective in the early stages, and patient awareness may provide psychological relief, incentive to pursue financial and advance care planning, access to early counseling, and the option to participate in research. ¹⁴

However, when genetic testing is performed, patients must be fully informed as to the risks and benefits. Genetic testing should be conducted with a protocol for pretest and posttest counseling that affords the opportunity to fully explore the personal meaning regarding a positive or negative test result and to make an informed decision about obtaining the test. ⁴ Testing involves potential risks to patients, including the fact that the results could be emotionally upsetting and stressful, might influence the patient’s ability to obtain insurance, and may affect employment. ¹⁴ Patients may misunderstand a test result and think a positive or negative result is absolute assurance that they will or will not develop dementia. In addition, long-term care insurance may discriminate based on the results of the genetic testing. Genetic testing affects children of the patient, potentially causing psychological distress if they find out they are at greater risk of a debilitating and terminal condition. The informed decision discussion should also include logistical issues, such as costs and planning for future care contingencies.

If genetic testing is performed, counseling must be completed and documented with a signed informed consent document placed in the medical record. The laboratories that perform genetic testing should not process any specimen without a written informed consent. Unfortunately, many laboratories will conduct the test without proper documentation, even when it violates their own corporate policies. ¹⁵

In 2011, patients could bypass their providers for testing by purchasing a home genetic testing kit. ¹⁶ This kit contained basic information about what the genetic testing means but did not provide the level of detail that would be communicated by a physician who is familiar with the genetic, statistical, and psychological aspects of APOE testing. In addition, the kit did not provide any posttest consultation and counseling. The Food and Drug Administration recently suspended this program because of the inherent problems with not having a physician involved in genetic testing.

With the current increase in genetic testing, primary care providers, geriatricians, neurologists, and neuroradiologists need to be well-versed in the details of genetic testing and counseling for AD. A lack of awareness can cause significant suffering to patients and their families due to the possible disclosure of unwanted medical information. The following case subsequently illustrates the potential for adverse effects when genetic counseling and informed consent protocols are not followed.

Case Presentation

A 55-year-old white female with short-term memory loss for 2 years presented to the neurologist, as a referral from her primary care physician for confirmation of the diagnosis of frontotemporal dementia. She had neuropsychological testing 3 months before presentation to the neurologist, which showed frontal dysfunction suggestive of frontotemporal dementia with deficits in attention, concentration, and working memory as well as slow processing speed. The patient reported difficulty recalling conversations and trouble with finances. Her husband observed episodes of staring and eyelid fluttering. Electroencephalogram showed bitemporal epileptiform activity, worse on the left. She was started on antiseizure medication. Magnetic resonance imaging (MRI) of the brain was read as normal. Folstein Mini-Mental Status Examination was 23 of 30. ¹⁷ Buschke Memory Impairment Screen was 4 of 8, indicative of poor memory, and she had poor topographical orientation on a map of the United States. ¹⁸ Clock drawing task was unremarkable except hands were of equal size. Spontaneous speech was normal but she had trouble naming object parts. Her ability to perform simple calculations was poor. Her eye movements were full and conjugate; however, pursuit movements were jerky in the horizontal and vertical directions. The remainder of the neurological examination was normal.

During the neurologist’s interview, the following history was obtained from the patient and family: the patient held a master’s degree in psychology. She never smoked nor drank alcohol. The patient was married and had 3 children who were in their 20s without medical problems. She lived at home with her husband. The patient’s mother, age 79, was alive and healthy. Her father, age 85, was alive but with kidney problems. She had 2 brothers and 4 sisters, ranging in age from 50 to 62 years old, with no neurological or psychiatric history.

The initial working diagnosis was frontotemporal dementia. Since the patient was relatively young, the neurologist ordered the following: a positron emission tomography (PET) scan with 18-F fluorodeoxyglucose; complete blood count; comprehensive metabolic profile; folate level; antithyroglobulin and antithyroperoxidase antibodies; thyroid stimulating hormone; antinuclear antibody; C-reactive protein; vitamin B12 level; Lyme titer; and a fluoroscopy-guided lumbar puncture with fluid sent for total protein, glucose, venereal disease research laboratory test, culture, and cell count, and the Athena Diagnostics Phospho-Tau/Total-Tau/Ab 42 CSF Analysis & Interpretation to measure cerebrospinal fluid (CSF) amyloid-β (Aβ) 1-42 and τ levels. ¹⁹ It is important to note that the Athena Alzheimer’s panel was completely paid for by the patient’s insurance.

During the lumbar puncture, performed under fluoroscopic guidance, the neuroradiologist ordered APOE genetic testing (without the knowledge or agreement of the neurologist or consent of the patient). Blood was obtained and sent to Athena Diagnostics for analysis. The patient received no genetic counseling before the blood was drawn, and there was no documented informed consent. Per the referring neurologist, the patient had sufficient decision-making capacity for medical decisions. Additionally, the family was not consulted about the genetic testing. The neurologist was unaware that the test had been ordered until the results became available.

The PET scan showed diminished glucose metabolism in the bilateral parietal and temporal regions suggestive of AD. The CSF Athena panel showed low Aβ 1-42 and high τ, strongly indicative of AD. The APOE test revealed that the patient’s genotype was ∊4/4. Other laboratory tests were normal. These results indicate that AD was the likely cause of the dementia. Assuming both of the patient’s parents are ∊4 heterozygotes, each of the patient’s siblings has a 75% chance of having at least 1 ∊4 allele (100% if either parent is 4/4). Each of the patient’s children has a 100% chance of having at least 1 APOE ∊4 allele. The cause of AD in this case was unlikely due to a rare autosomal dominant mutation since both of her parents are living without signs of dementia, and there is no family history of the disease.

The neurologist did not request APOE genetic testing because it would not substantially increase diagnostic accuracy. Additionally, he perceived that it could cause undue stress for her children if the genotype was 4/4 and could generate a sense of guilt in the patient and/or her parents for transmitting the ∊4 allele. At the second visit, following the acquisition of the laboratory results, the neurologist debated whether to inform the patient and her family of the genetic testing results because (1) he did not order the genetic testing; (2) the patient and family had not given their consent for the test to be done; and (3) the information may not be of value to the adult children, as there is nothing that one can do with the APOE genotype information to lower one’s Alzheimer risk, other than widely-recommended healthy behaviors regarding diet and exercise that should be recommended to everyone. ¹⁰ However, the neurologist was concerned about his responsibility not to withhold information from the family.

The neurologist met with the patient and her adult children, informing them that the diagnosis was highly likely to be AD, based solely on the MRI, PET scan, and CSF findings. He reviewed all of these test results and then told them about the availability of APOE genetic testing and the risks and benefits of such testing whether the results are positive or negative. He explained the risks of undue stress, no cure, no preventive measures, and no guarantee of predictability. He explained the benefits of potentially knowing the diagnosis with even more certainty and helping future generations. He informed them that the results of this genetic test would not change the current treatment course or the diagnosis. Based on the neurologist’s recommendation, the patient and adult children declined genetic testing. The neurologist concurred with their decision. The neurologist did not inform the patient and the family of the existence or results of the APOE genetic testing. He also consulted with the insurance company who paid for the test and was informed that they had not informed the patient that the test had been completed. He consulted with a geneticist on faculty at the University who concurred that it was not indicated to inform the children as the neurologist had told them about the availability of this test, and they had not indicated an interest. The neurologist also spoke with the Ethics Committee and the patient’s primary care provider who all agreed that it was not indicated to disclose these results. The neurologist’s perspective was that not disclosing this information, especially when not requested, mitigated genetic testing harm, as described by Karlawish. ²⁰

Ethical Considerations

The ethical considerations in this case are manifold. The main concerns are on the ethical principles of respecting persons (patient autonomy), promoting the patient’s benefit (beneficence), avoidance of harm (nonmaleficence), justice, and the virtue-based considerations of truth-telling and trust. ²¹ When ordering an APOE genetic blood test, a signed informed consent document must be explained to the patient and verified for their understanding of the test under consideration by an evidenced means of consent (in this case, a signature on the form). The neuroradiologist did not provide this information nor was a form offered for signature. It was later determined that the neuroradiologist independently devised the protocol whereby he would always perform APOE genetic testing automatically (without patient consent) when AD testing for CSF was performed. Motives of the neuroradiologist can be inferred, such as (1) consent was received for the more invasively procured CSF studies (Aβ 1-42 and τ levels) and that blood testing is implied or (2) that the informed consent would be done by the neurologist later. Yet, these cases inadequately safeguard the patient’s autonomous right to consent to a test that has far-reaching meaning not only for her but also for her descendants.

Regardless of whether the neuroradiologist rationalized this practice as easier or implied, it cannot be ethically defended as it violates the patient’s autonomy. Each APOE genetic test requires explicit consent, given the ramifications of a positive test, requiring pretest genetic counseling and a valid signed informed consent process. There was no demonstrable urgency or ethical rationale for not providing such consent to the patient. Even worse, it was subsequently learned that similar abridgements of consent had occurred by this neuroradiologist with other patients in drawing APOE blood testing without their consent. Because of this case study, the neuroradiologist ended the protocol to draw the genetic test automatically and agreed that he should not unilaterally order genetic testing at any time. This protocol was a clear violation of the standard of care regarding respect for persons in genetic testing (see subsequent).

The patient was at risk of harm in such a circumstance, rather than benefit as the testing was done without her permission, a violation of beneficence and nonmaleficence claims. The “assault” (unknown by the patient) is the invasion of privacy of removal of bodily fluids with knowledge gained that will have far-reaching impact that could be harmful. The neurologist did not feel that the results should be removed from the chart as it would be unethical to alter a medical record. Electronic health records, and medical records generally, have a propensity for moving information in unintended ways—the patient’s genetic risk noted in the medical record is now accessible by the patient’s physician and potentially by a proxy, her offspring, and their insurers. The consequences of a positive test, once errantly discovered, could be emotionally devastating, with the shock of such news being more harmful than if valid consent had been received. The patient’s offspring could also be harmed through receiving test results that reveal risk of future AD. If the patient, her family, or any third party ever requests her records, then they would see the results of the genetic testing. The adult children would then know that they are carriers of an ∊4 allele and that this information was not shared with them—with the resultant consequences of a breach of trust. Also, if a new provider requests medical records, then the new provider may reveal the genetic test results. The harm of this land mine of unrequested medical knowledge could have a detrimental impact on their concept of future health, their insurability, and their perceived trust in the medical profession.

In the aftermath of the neuroradiologist’s actions, the referring neurologist believed that offering the now known APOE genetic testing safeguarded his responsibility to honor the patient’s autonomous consent or refusal of the APOE test, without revealing what had been done by the neuroradiologist. Since patient and family refused the test, he believed that the completed result offered no benefit to the patient or her children). His perception was that all parties could be harmed, rather than helped, by learning the results of the APOE genetic testing. The neurologist made the diagnosis of AD before the genetic test results were available. This decision makes the virtues of truth-telling and fidelity to trust relevant, as the family trusted the neurologist, who had already made the clinical diagnosis of AD in the patient and who had strong suspicions that this was indeed the correct diagnosis to be validated by the requested laboratory testing. As such, family members may then have the opportunity to gain from this metaphorical “fruit from the poisonous tree” in order to better prepare themselves for the future risk of Alzheimer’s and to consider proactive treatment when such opportunities avail themselves in future medical interventions.

One might question whether the neurologist had a duty to report the genetic testing results to the patient and family. Some might suggest that he did not. ^12,14 After all, there is no duty to report information that will not impact the diagnosis or course of treatment for the patient or to cause the offspring unnecessary worry. The decision to perform genetic testing should be a personal one between the physician and the patient. One could also argue that the neurologist also had an autonomy-based obligation to divulge this information (as the genetic test results are the property of the patient). ²² Further, there is a virtue-based obligation (see earlier) to divulge the protocol of the neuroradiologist that the test had been performed without permission, that the results were available if requested, and that the system-based errors that resulted in the ethical and procedural lapses had been addressed by the institution. By extension, the family had a right to know that such knowledge could impact their future health, by both justice-based consideration and family-based consideration. ²³ A preventive ethics strategy in genetic testing would be to utilize a family covenant, a health care agreement between physician, patient, and family members, to proactively set parameters of how knowledge is shared within the family and how it should be disseminated. ²⁴

Standard of Care Considerations

In June 2011, guidelines were published by the American College of Medical Genetics and the National Society of Genetic Counselors to assist health care providers in making decisions about appropriate management of genetic concerns related to AD. ²⁵ The guidelines state that “genetic testing for AD should only occur in the context of genetic counseling and support by someone with expertise in this area.” ²⁵ The guidelines generally discourage APOE testing in asymptomatic people but do allow for testing “at the clinician’s discretion.” ²⁵ These guidelines had not yet been issued at the time the case occurred. However, the principles within these guidelines were available as standard of care since 1997 when a consensus statement explained that “except for autosomal dominant early-onset families, genetic testing in asymptomatic individuals is unwarranted. Use of APOE genetic testing as a diagnostic adjunct in patients already presenting with dementia may prove useful but it remains under investigation. The premature introduction of genetic testing and possible adverse consequences are to be avoided.” ²⁶ Therefore, home genetic testing in asymptomatic people is not recommended.

In 2009, the Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study Group randomly assigned 162 asymptomatic adults who had a parent with AD to receive the results of their own APOE genotyping or not to receive such results. The REVEAL Study Group found that the disclosure of APOE genotyping did not result in significant short-term psychological risks to the patient. ²⁷ The REVEAL study also found that persons who learned about their APOE genotype through an education-and-disclosure protocol did not have greater symptoms of anxiety, depression, or test-related distress than those not receiving such information. ²⁷ However, the patient in this case did not have any education about testing and there was no disclosure protocol in place to ensure minimal psychological harm. Therefore, when the test results came back to the neurologist, he did not immediately disclose the results. Instead, he educated the patient and family about the genetic testing options in order to prevent potential anxiety, depression, or distress.

Conclusion and Practical Considerations

In the case presented, the neuroradiologist, who was not an expert in AD, inappropriately performed APOE genetic testing without requisite or genetic counseling or informed consent. Further, Athena Diagnostics performed the genetic testing without a signed informed consent document, violating their own protocol. The genetic testing demonstrated a case in which multiple errors resulted in a genetic test finding with potentially negative consequences for the patient and family, which then required redress by the neurologist regarding whether the test ever would have been wanted, and whether it bore relevance to the patient’s future health or that of her progeny.

There may be a large number of people who will want genetic testing for AD as there is more concern over the illness. A study published in 2004 showed that 24% of contacted participants wanted genetic counseling regarding AD and 64% of self-referred participants wanted the counseling. ²⁸ Predictive genetic testing performed by those not trained in genetics will very likely recur, as in this case. Yet, genetic testing should never be performed unless the patient has been given the opportunity to consent to such testing by a professional with fundamental genetics training on the meaning of the test offered. Situations exist when genetic testing and counseling are appropriate, with the ideal setting of counseling always being provided by a genetic counselor or a geneticist. However, there is a significant shortage of genetic counselors and geneticists in the United States. ¹⁴ Most nongenetics professionals do not believe that they are prepared to provide genetic counseling and testing unless they receive further requisite training to do so. Therefore, health care providers need to know the guidelines surrounding their responsibilities on genetic testing and counseling and should be educated about the risks and benefits of their playing this role in the absence of a genetic counselor. Only with this training can providers mitigate the harm genetic testing can do to their patients and their patients’ children. There is a need to educate physicians and train more genetic counselors about genetic testing for Alzheimer’s dementia because this is a disease that is becoming more prevalent as our population ages.

This case confirms that safeguards to genetic testing should be generally established as standards of care and that APOE testing is a herald case. Formal education should be provided to primary care physicians, geriatricians, neurologists, and neuroradiologists regarding the proper ethical and clinical uses of genetic testing. Genetic testing should always be preceded by a genetic counseling discussion between the patient, his/her family, and a provider experienced in the discussion, as well as an informed consent from a patient with known decisional capacity or from the health care surrogate. These safeguards will prevent future inappropriate genetic testing due to lack of an informed consent discussion.