Clinical Use of Alzheimer Disease Biomarkers: Legal, Ethical, and Social Considerations

Alzheimer disease (AD) biomarkers are moving out of the research space and into the clinical realm.¹ Food and Drug Administration–approved therapies that target disease pathology rely on biomarker tests to identify individuals who meet eligibility criteria for therapy. These advancements combined with developments in biomarker research have driven a need for clinical guidelines. To this end, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) distributed draft diagnostic guidelines² to integrate AD biomarkers for clinical use (see recent article by Pleen et al). The NIA-AA draft guidelines focus on developing standards for the clinical interpretation of AD biomarkers when diagnosing and treating AD; however, implementation also requires incorporating legal and ethical standards and practices to maximize potential benefits while minimizing potential burdens or harms. In this article, we provide a discussion of legal, ethical, and social considerations that are relevant to adopting AD biomarkers as part of clinical care.

Use of AD Biomarkers in Medical Care vs Clinical Research

Medical care aims to improve the health of individuals. This objective entails legal and ethical duties and rights that primarily exist between clinicians and patients. Clinical research aims to produce generalizable knowledge that advances scientific understanding of disease toward preventative or therapeutic interventions. Researchers are responsible for prioritizing participant protection, but they have no legal or ethical responsibility to provide direct benefits (e.g., treatments or improved health outcomes) to research participants.

AD biomarkers are utilized differently in research and clinical settings. AD biomarkers have been consistently used as research tools to establish research-confirmed diagnosis,³ determine eligibility for clinical trials,⁴ and track disease progression. In clinical care, AD biomarkers may be used for diagnostic or disease staging purposes. Diagnostic uses can be further characterized to include triage and confirmatory uses.^2,5 Triaging is used to identify people who should receive follow-up evaluations; confirmatory uses aim to make a diagnosis of or rule out AD, often with a goal of establishing eligibility for therapies.⁵ Similarly, whereas legal, ethical, and social research on AD biomarkers within observational studies and clinical trials provides preliminary insights that can guide the clinical medical use of AD biomarkers, novel issues will emerge due to differences in clinical setting and governance.

Beginning with Fairness

Fair and equitable adoption of AD biomarkers in clinical care should drive implementation strategies and decisions. Three issues are foreseeable in clinical adoption: (1) who will have access, (2) how a test performs across populations, and (3) how to ensure that resources are distributed equitably after biomarker testing. Blood-based biomarkers (BBBs) have been lauded for expanding access to testing by providing scalable approaches to detect disease pathology that can be adopted in diverse settings (eg, primary care clinics).⁶ However, this alone does not ensure fairness. Considerations of how implementation strategies, policy decisions (eg, Centers for Medicare & Medicaid Services coverage), and clinical guidelines may mitigate or exacerbate a disproportionate benefit or burden across populations should be central to clinical processes. In the following, we incorporate these considerations when evaluating benefits, burdens, and disclosure practices.

Establishing Individual Benefit

“Benefit” involves optimizing health outcomes for individual patients (eg, cure, mitigating symptoms, quality of life) and is a threshold factor in establishing whether clinical adoption of AD biomarker testing is ethically justified.⁷ A more comprehensive account of “benefit” is needed which encompasses more than clinical therapeutic decisions which justify AD biomarker testing based solely on the outcomes of testing.

The availability of disease-modifying therapy (DMT) (eg, lecanemab [Leqembi; Eisai, Nutley, NJ]) provides a paradigm case of therapeutic benefit. Appropriate-use criteria for lecanemab recommend treatment of individuals with mild cognitive impairment or moderate dementia with evidence of amyloid deposits on positron emission tomography or cerebrospinal fluid (CSF) testing.⁸ These criteria are consistent with payor decisions that are likely to limit coverage for biomarker testing to indications that affect clinical management.⁹ However, restricting “benefit” to therapeutic benefit would limit biomarker testing to people who meet these criteria and do not have exclusion criteria (eg, comorbid cardiovascular diseases)⁸ and would exclude people who may otherwise benefit from testing for nontherapeutic reasons, including to establish certainty regarding diagnosis and future planning purposes.¹⁰ Restricting access to biomarker testing on the basis of therapeutic benefit could have consequences for the potential value of testing as a triage in primary care settings.

Biomarker testing may be useful in primary care settings to determine whether an individual should be seen by a specialist. However, if that individual is ineligible for treatment because of age, body mass index, or a comorbid condition, the testing clinician would then need to consider whether it is ethically supportable to offer biomarker testing. A decision not to test because of a perceived lack of therapeutic benefit could preclude the individual from accessing other services that are often available through specialty centers (eg, increased monitoring, social work services, genetic testing and counseling).

It is foreseeable that people may seek out biomarker testing before symptoms emerge, particularly if they carry a known genetic marker for AD or have a strong family history. There are no recommendations or guidelines that support AD biomarker testing in asymptomatic individuals.^11,12 Under existing use criteria for DMTs, this population would not be eligible for treatment, limiting the benefit of testing. If benefit is reframed to consider personal use or nontherapeutic clinical decision making, there could be justifications that support asymptomatic biomarker testing. However, the potential consequences (as described in the following) are likely more substantial for those without symptoms.

The Relevance of Testing Options

Advances in biomarker testing have provided clinicians with multiple options regarding test selection (eg, biologic focus, test modality), which is primarily a clinical decision. There are ethical drivers and consequences associated with these decisions, particularly given improved performance among BBB tests.⁶ BBBs are emerging as clinically useful tools with important advantages over CSF and imaging markers in terms of accessibility, scalability, and invasiveness.¹³ As researchers work to validate BBBs against CSF and imaging results, characteristics that have ethical salience regarding clinical adoption (eg, accessibility, scalability, accuracy, invasiveness) also should be considered (see Table).

The accessibility of a test is determined by cost and payor coverage, facility resources and capabilities, and health care provider capacity (eg, time and training required to offer testing and disclose results). Scalability references the capacity to increase the capability of testing through enriching the numbers of health care providers providing and interpreting testing and thus the people who would gain access to testing. BBBs are being championed as offering increased accessibility by increasing the scalability of biomarker testing. However, although use of BBBs removes the need for specialized technical equipment (eg, scanners), scalability may be limited by health care capacity to offer and disclose test results, storage facilities, and access to laboratories equipped to analyze results.¹⁴ Research is needed to understand whether primary care and nondementia specialty centers are prepared to offer biomarker testing—specifically BBB testing—as part of regular practice. Previous research has demonstrated that gerontologists feel unprepared to counsel people on APOE genetic testing results or to help interpret direct-to-consumer test results.¹⁵ Primary care clinicians and other nondementia specialists may report similar limitations regarding biomarker testing.¹⁴

Biomarker testing is most ethically supportable in the context of tests that produce the highest degree of accuracy with the least invasiveness and lowest risk or burden. Clinical adoption requires a full understanding of test accuracy, which will be central to validate informed consent practices. People should be informed of rates of false positives or false negatives and the potential consequences. False positives could lead to inappropriate therapeutic decisions and patient distress. False negatives could result in increased testing to identify other causes of cognitive impairment, false assurance, and missed opportunities to seek timely therapeutic treatment. Challenges associated with test accuracy (eg, interassay variability, lack of standardized cutoff points) hinder evaluation of test performance.^16,17 Other factors may also affect test accuracy, including individual comorbidities (eg, cardiovascular disease).¹⁸ Test accuracy also may vary among different racial and ethnic groups, which could exacerbate existing disparities.¹⁹

Burdens or harms, including invasiveness, associated with a given test modality are important characteristics to share with patients. The characteristic of potential harm has an inverse relationship with accuracy within the context of the proposed purpose of a test. A test that is highly accurate may still be ethically questionable if the harms or burdens of the test outweigh the potential benefits. Conversely, a test that is minimally invasive with few harms or burdens is only ethically supportable if it is also sufficiently accurate for its proposed purpose. BBB tests offer major advantages over imaging and CSF measures of AD pathology, because they are less invasive. This reduces their associated risk, burden, and potential harm. The requisite accuracy of any type of AD biomarker test may depend on the proposed medical use. For example, if testing is being proposed for triage purposes (in which the assumption is that further testing will follow), then the reduced burden or harm associated with BBBs could justify offering a test with lower accuracy. This may not, however, be the same outcome if testing is for confirmatory purposes, where the outcome of the test could drive therapy decisions.

Disclosing Results and the Potential Consequences

Clinical disclosure of AD biomarker results raises novel clinical and ethical issues. In contrast to research disclosure practices, clinical disclosures are a required aspect of care and include documentation of results in the medical record. The 21st Century Cures Act mandates immediate individual access to health records.²⁰ This hinders clinicians’ capacity to provide counseling before people access their test results. Disclosure practices developed in research settings assume models for pretest and posttest counseling and timing.²¹ In these models, researchers can assess for increased risks and prepare participants for consequences associated with biomarker disclosure. Furthermore, research results have additional privacy and confidentiality protections that limit access by third parties (eg, insurers).²² Knowledge of disclosure practices in the research setting to predict potential risks (eg, distress, stigma, discrimination) can be used to develop disclosure tools for the clinical setting.

Researchers have consistently considered distress and psychologic safety as consequences of disclosing genetic and biomarker status.^23-25 Research results on distress and psychologic safety associated with disclosure have varied. Some have indicated that disclosure of risk to asymptomatic individuals results in preliminary distress.²³ Disclosure outcomes of genetic and biomarker status may vary depending on individual-level characteristics (eg, asymptomatic vs symptomatic, known family risk).^4,12,26,27 How clinical disclosure will diverge is unknown (ie, whether disclosure by means of electronic health record will affect people’s experiences with the process). Distress may also be accompanied by stigma and the risk of discrimination. Stigma associated with AD has been well established.²⁸ AD biomarker testing advancement may shift this stigma, particularly for those who are asymptomatic or early in the disease process and now carry labels associated with being at risk and confirmed to have AD pathology.²⁹

Documentation of AD biomarker status in the medical record may increase risks of discrimination. Health privacy and confidentiality safeguards (eg, Health Insurance Portability and Accountability Act) protect clinical information from broad disclosure.³⁰ However, third parties may be able to access health information legally in limited circumstances. For example, long-term care insurers have explicit permission to access and use health records during underwriting procedures.³¹ Similarly, there may be circumstances where employers can learn of an individual’s biomarker status. Furthermore, disclosure to third parties could result in discrimination (eg, ableism, ageism, or infantilization of the diagnosed individual).

With the advancement of AD biomarker disclosure and use in the clinical setting, it is prudent to set and validate standard workflows for health care workers to follow. A workflow should include consenting practices to ensure that people are informed of potential consequences of test results and supported after disclosure. In primary care settings, workflow should consider the limitations of clinical resources (eg, patient navigators may be limited to specialty care settings).

Conclusion

NIA-AA draft diagnostic guidelines help guide the increase in AD biomarker test use in clinical settings, but these guidelines are not inclusive of the important examination of legal, ethical, and social issues. Equitable and appropriate adoption of testing should be derived from goals of maximizing individual benefit, testing modality choice and access, and validating frameworks for consent, disclosure, and counseling.