6. Ethical challenges in the disclosure of biomarker results

#### 6.1. Introduction

By and large, the medical community tends to blur the distinction between that which is kept strictly for research, and that applied in routine clinical practice. At present, the boundaries between current research guidelines in dementia research and clinical practice are not distinct. Research criteria have a strong potential to impact clinical practice, such that terminologies used in research settings easily become adopted into routine clinical practice.

Biomarkers in dementia give risk information only, and results can be inconclusive. Until a cure is developed, the distance between advancements in diagnosis and treatment continues to grow. A positive result is not a diagnosis. Not all with positive biomarker results will develop AD. Potential harms with study participation include confusion over inconclusive results, being given wrong diagnoses, stigmatisation, exploitation, discrimination, negative affective reactions [61], escalation of insurance premiums [62], loss of the right to drive, additional work conditions, and over-protection by law which can disadvantage employers.

### 6.2. Disclosure of biomarker results

Disclosure of AD biomarker results is an important consideration in dementia trials. Study designs that reveal increased risk may facilitate willingness to participate [63]. People participate in studies because by knowing, they may potentially lower their risk, so they may give their time and effort [64]. Similarly investigators are more in favour of disclosing scan results to MCI than to healthy controls [65]. Communicating AD risk information has wideranging ethical, psychological, behavioural, and social implications. People have different views about whether or not they actually want to learn the results. Periodic assessments of mood and well-being, providing access to appropriate care if there are problems, and presence of a designate partner for support are important considerations for participation in studies.

information. While disease modifying treatment is currently only available by participating in drug trials and may offer a glimmer of hope, it does have side effects and is not guaranteed to work. Clinicians need to be sensitive to the negative impact breaking bad news can have on patients, and be ready to provide support, like disease counselling. Regardless of whether patients want to know, the disease will progress, and confidently diagnosing AD will help

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The need to mitigate the potential harm must be balanced by the patient's right to know their result. Cognitive biases in affective forecasting may over- or under-estimate reactions to negative events. Empirically validated methods of disclosing risk information can inform practice and policy, and avoid speculation of how long and how intensely negative reactions will last following disclosure. The full long term downstream effects of finding out and of how individuals and families interpret and handle the information is not known, so these people should

One study that followed 148 cognitively normal people participating in a randomised clinical trial of genetic testing for Alzheimer's disease for 1 year after risk assessment and E4 disclosure showed that those tested as positive were 5.76 times more likely to have altered their longterm care insurance than those who did not receive E4 genotype disclosure [62]. Nonetheless the broader literature suggests that receiving a diagnosis of MCI or AD did not increase depression or anxiety in patients nor their carers in the short term, and anxiety often decreased [66]. One study that assessed the impact of genetic risk assessment on adult children of people with AD showed a slight increase in the impact of event between E4 carriers and non-carriers at 6 weeks, but the effect washed out at 6 months [67]. Hence E4 status can be

Other than finding a cure, promoting healthy brain ageing is also important. This can be done by determining and promoting those factors that promote longevity and healthy brain ageing. Promotion involves staying mentally and physically active, staying socially engaged, and controlling cardiovascular risk factors like weight, blood pressure, cholesterol, and blood

The need to be persistent, to innovate and to move forward is urgent despite numerous challenges. Whether we choose to address the conundrums or ignore them because of technical difficulties, the tsunami of the dementia epidemic will hit us in a few short years. Fortunately the dementia field has been very motivated. In spite of the numerous challenges in developing new models of understanding, diagnostic criteria, clinical markers, biomarkers, treatment, and improving diagnostic accuracy, the field is marching towards addressing, and intervening in,

Finally, attention to the nuances and caveats, and applying little tweaks in study designs can

improve efficiency and study quality, reduce risk, and shed new insights.

revealed safely to patients without risk of long-term depression or anxiety.

them and their relatives make firm plans.

be followed to observe the effects of disclosure.

sugar, quitting smoking and having a balanced diet.

7. Final word

AD in its early stages.

The practice in ADNI has been not to disclose biomarker results to participants. Yet being in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study means that a participant is declaring that he has a positive amyloid PET scan. No disclosure would be needed in the A4 study if it was designed as a three-arm randomised control trial with normal controls. However this would require greater sample sizes escalating costs and complicating the informed consent process.

Although biomarker use had been limited to research, clinicians in tertiary care are often involved in biomarker research, and have an interest in the biomarker result to guide management of their patients. Before biomarkers were officially approved for routine clinical use, specialist clinicians were already applying biomarkers results informally in clinical practice with the informed consent of their patients [65]. It was openness for accumulating such experiences that drove thinking and enabled planning in biomarker validation studies. Clinicians are motivated to refer their patients for biomarker research studies, and patients are motivated to participate, when they can benefit from obtaining a copy of the results even if the biomarkers are not validated.

The more opportunities there are to use biomarkers in the clinical setting, the more we are going to find cases of amyloid PET scans showing intermediate levels of amyloid in the brain, particularly as cases requiring biomarkers to improve the diagnostic work-up tend to present with some degree of diagnostic dilemma. While these cases are the hardest to diagnose, they are also potential opportunities to further our understanding.

Both positive and negative biomarker results can benefit patients and families. A negative result brings relief, and unnecessary further clinical testing is avoided. A positive result when handled well enables early decision making when participants still have capacity, efficient channelling of resources, and it also encourages healthy lifestyle change.

#### 6.3. Evidence-based disclosure practice

The problem with AD is not merely whether one has plaques in the brain or not, or whether people will want to know if they have the disease, but also how long do they have before they have to move into residential care, and if they do have the disease whether they can be eligible for costly drug treatment. One other consideration is what people will do once they get that information. While disease modifying treatment is currently only available by participating in drug trials and may offer a glimmer of hope, it does have side effects and is not guaranteed to work. Clinicians need to be sensitive to the negative impact breaking bad news can have on patients, and be ready to provide support, like disease counselling. Regardless of whether patients want to know, the disease will progress, and confidently diagnosing AD will help them and their relatives make firm plans.

The need to mitigate the potential harm must be balanced by the patient's right to know their result. Cognitive biases in affective forecasting may over- or under-estimate reactions to negative events. Empirically validated methods of disclosing risk information can inform practice and policy, and avoid speculation of how long and how intensely negative reactions will last following disclosure. The full long term downstream effects of finding out and of how individuals and families interpret and handle the information is not known, so these people should be followed to observe the effects of disclosure.

One study that followed 148 cognitively normal people participating in a randomised clinical trial of genetic testing for Alzheimer's disease for 1 year after risk assessment and E4 disclosure showed that those tested as positive were 5.76 times more likely to have altered their longterm care insurance than those who did not receive E4 genotype disclosure [62]. Nonetheless the broader literature suggests that receiving a diagnosis of MCI or AD did not increase depression or anxiety in patients nor their carers in the short term, and anxiety often decreased [66]. One study that assessed the impact of genetic risk assessment on adult children of people with AD showed a slight increase in the impact of event between E4 carriers and non-carriers at 6 weeks, but the effect washed out at 6 months [67]. Hence E4 status can be revealed safely to patients without risk of long-term depression or anxiety.
