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Current Topics in Care

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

Christian D. Furman, MD, MSPH, AGSF1, Lori A. Earnshaw, MD2, David J. Doukas, MD3, Lindsay A. Farrer, MD4, and Robert P. Friedland, MD3

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.

Keywords genetic testing, Alzheimer’s disease, ethics, informed consent

Introduction

Twenty years ago, the apolipoprotein E (APOE) e4 allele was found to confer susceptibility to late-onset Alzheimer’s dis-

ease (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 e4 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 e4 carriers surviving to age 80 years do not develop AD.2,3 Thus, APOE e4 is best viewed as a genetic risk factor for AD rather than a genetic

marker of the disease4 because the risk of developing AD for

individuals with at least 1 e4 allele by age 80 years is esti- mated to be 29% compared to 9% for individuals lacking e4.5

Among caucasians, the odds of developing AD are 2 to 3 times

higher for e4 heterozygotes and 12 to 14 times higher for e4 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 commu-

nity 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

1 Department of Family and Geriatric Medicine, University of Louisville School

of Medicine, Louisville, KY, USA 2 Department of Internal Medicine, University of Louisville School of Medicine,

Louisville, KY, USA 3 University of Louisville School of Medicine, Louisville, KY, USA 4 Boston University Schools of Medicine and Public Health, Boston, MA, USA

Corresponding Authors:

Christian D. Furman, MD, MSPH, AGSF, Department of Family and Geriatric

Medicine, University of Louisville School of Medicine, 401 E. Chestnut St. Ste.

170; Louisville, KY, USA.

Email: [email protected]

Lori A. Earnshaw, MD, Department of Internal Medicine, 550S. Jackson St,

3rd Fl ACB, Louisville, KY, USA.

Email: [email protected]

American Journal of Alzheimer’s Disease & Other Dementias®

2014, Vol. 29(7) 590-595 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514525829 aja.sagepub.com

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 per-

sonal 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 com-

pleted and documented with a signed informed consent docu-

ment placed in the medical record. The laboratories that

perform genetic testing should not process any specimen with-

out a written informed consent. Unfortunately, many labora-

tories 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 psy-

chological 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 dis-

closure 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. Electroence-

phalogram 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 unre-

markable 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 prob-

lems. 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; comprehen-

sive 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 Diag-

nostics Phospho-Tau/Total-Tau/Ab 42 CSF Analysis & Inter-

pretation to measure cerebrospinal fluid (CSF) amyloid-b (Ab) 1-42 and t 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 con-

sent of the patient). Blood was obtained and sent to Athena

Diagnostics for analysis. The patient received no genetic coun-

seling before the blood was drawn, and there was no documen-

ted informed consent. Per the referring neurologist, the patient

Furman et al 591

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 Ab 1-42 and high t, strongly indicative of AD. The APOE test revealed that the patient’s

genotype was e4/4. 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 e4 heterozygotes, each of the patient’s siblings has a 75% chance of having at least 1 e4 allele (100% if either parent is 4/4). Each of the patient’s children has a 100% chance of having at least 1 APOE e4 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 accu-

racy. 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 e4 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 chil-

dren, as there is nothing that one can do with the APOE geno-

type 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 mea-

sures, and no guarantee of predictability. He explained the ben-

efits 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 cur-

rent treatment course or the diagnosis. Based on the neurolo-

gist’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 (benefi-

cence), 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 con-

sent document must be explained to the patient and verified for

their understanding of the test under consideration by an evi-

denced 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 neu-

roradiologist independently devised the protocol whereby he

would always perform APOE genetic testing automatically

(without patient consent) when AD testing for CSF was per-

formed. Motives of the neuroradiologist can be inferred, such

as (1) consent was received for the more invasively procured

CSF studies (Ab 1-42 and t 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 permis-

sion, a violation of beneficence and nonmaleficence claims.

The ‘‘assault’’ (unknown by the patient) is the invasion of pri-

vacy of removal of bodily fluids with knowledge gained that

will have far-reaching impact that could be harmful. The neu-

rologist did not feel that the results should be removed from the

chart as it would be unethical to alter a medical record. Elec-

tronic health records, and medical records generally, have a

592 American Journal of Alzheimer’s Disease & Other Dementias® 29(7)

propensity for moving information in unintended ways—the

patient’s genetic risk noted in the medical record is now acces-

sible 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 devastat-

ing, 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 e4 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 refer-

ring 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, with-

out 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 chil-

dren). 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 vir-

tues of truth-telling and fidelity to trust relevant, as the family

trusted the neurologist, who had already made the clinical diag-

nosis 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 diagno-

sis or course of treatment for the patient or to cause the off-

spring 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 per-

formed 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 insti-

tution. 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 pre-

ventive 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 Col-

lege 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 gener-

ally discourage APOE testing in asymptomatic people but do

allow for testing ‘‘at the clinician’s discretion.’’25 These guide-

lines 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 unwar-

ranted. 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 test-

ing without requisite or genetic counseling or informed con-

sent. Further, Athena Diagnostics performed the genetic

testing without a signed informed consent document,

Furman et al 593

violating their own protocol. The genetic testing demon-

strated 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 neurol-

ogist 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 par- ticipants 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 oppor-

tunity to consent to such testing by a professional with funda-

mental genetics training on the meaning of the test offered.

Situations exist when genetic testing and counseling are appro-

priate, with the ideal setting of counseling always being pro-

vided 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 guide-

lines 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 neu-

roradiologists 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 fam-

ily, and a provider experienced in the discussion, as well as an

informed consent from a patient with known decisional capac-

ity or from the health care surrogate. These safeguards will pre-

vent future inappropriate genetic testing due to lack of an

informed consent discussion.

Acknowledgments

The authors would like to thank Sharon Barrer, RN and Margaret

Feldman for their editorial assistance.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship,

and/or publication of this article.

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