Biomarker-Based Risk Prediction of Alzheimer’s Disease Dementia in Mild Cognitive Impairment: Psychosocial,Ethical,and Legal Aspects

Abstract

Background:

Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer’s disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied.

Objective:

The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI.

Methods:

In the empirical study, 100 MCI-patients and their close others will be recruited from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes.

Results:

The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed.

Conclusion:

The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation.

Keywords

Alzheimer’s disease biomarker caregiver dementia disclosure ethics mild cognitive impairment quality of life risk

INTRODUCTION

Dementia is associated with major personal, social, and economic burden [1]. It is estimated that due to the rapidly aging population the prevalence of dementia will rise up to 135.5 million individuals worldwide in 2050 [1]. Alzheimer’s disease (AD) is the most common cause of dementia.

AD is characterized by amyloid pathology ex-pressed as aggregated extracellular amyloid-β 42 peptide and amyloid plaques, as well as neurodegeneration related to intracellular neurofibrillary tangles composed of phosphorylated tau [2]. The pathophysiological changes of AD start decades before its symptom onset and can be identified by biomarkers. Current research and clinical criteria propose and define pre-dementia stages of the disease, which allow the identification of individuals at high-risk of developing AD dementia [3 –5].

As such, mild cognitive impairment (MCI) corresponds to a pre-dementia (prodromal) clinical AD stage and is an at-risk condition for dementia. MCI is defined as a clinical syndrome, where mild decline in cognition is present, but activities of daily living are still preserved [3]. MCI itself, however, can be caused by many conditions and is not always related to AD. Thus, only about 30% of MCI-patients develop AD dementia within three years after MCI diagnosis [6].

Today, advances in the field of cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarker diagnosis allow the identification of individuals at-risk for developing AD dementia long before the stage of dementia is reached. MCI with biomarker evidence for AD is associated with a highly increased risk of up to 90% for developing AD dementia within a limited number of years. In contrast, MCI without biomarker evidence for AD is only associated with a risk of lower than 10% to develop dementia in the next future [7]. Biomarker-based early AD detection is applied widely in research and also in clinical settings, and the demand by individuals with mild cognitive symptoms to undergo early disease detection and estimation of dementia risk is increasing.

With regard to diagnosis and treatment, literature indicates that AD biomarker assessments in individuals with MCI and dementia may lead to changes in clinical management [8 –12]. The Dutch research project Alzheimer’s Biomarkers in Daily Practice (ABIDE) has developed a biomarker-based prediction model, which allows a personalized AD risk profiling for individuals in pre-dementia stages [13]. Within the study, a Web-based tool has been designed to support clinicians, patients, and caregivers in the context of early AD biomarker detection [14]. The aim of the project is to provide personalized risk estimates of progression to dementia in order to facilitate the interpretation for clinicians, offer guidance for disclosure of AD biomarker test results and dementia risk, and support clinicians to engage patients in decision-making regarding the diagnostic workup of AD. Meanwhile, first initiatives developed recommendations for CSF and PET biomarker testing for AD in individuals at-risk of AD dementia for clinical and research purposes [15 –19]. These recommendations were mainly based on expert consensus processes, as empirical evidence on this topic from, for example, randomized clinical trials, is sparse. Along with recommendations to clinical indication of AD biomarker testing, counselling, and disclosure, advise on follow-up assessments such as potential effects on psychological outcomes are given. However, although effects on psychological features, such as depression, anxiety, and perceived stress, are considered, specific guidelines referring to a more comprehensive psychological and social assessment (e.g., quality of life, lifestyle changes, spirituality, attitudes, and expectations) including close others are missing, which goes back to scarce empirical data.

Apart from the ABIDE project, effects of AD biomarker testing and disclosure on patients and close others are becoming the focus of research [20 –27]. Interviews with cognitively healthy individuals with pathological amyloid PET results confirmed that about two-thirds understood their PET results correctly and further data depicted psychological safety and health behavior changes in order to improve brain health [21, 22]. Research on amyloid PET results disclosure on individuals with subjective cognitive decline (SCD) depict no significant effects on depression, anxiety, or stress symptoms on short- and long-term outcome one year after disclosure [24, 29]. Data on amyloid PET disclosure on individuals with MCI and mild dementia revealed mixed emotional results during interviews and no clinical relevant psychological risks on psychometric evaluation on short-term outcome [20, 27]. Recently published results from a randomized controlled trial of amyloid PET results disclosure in MCI revealed higher levels of distress after amyloid PET result disclosure among amyloid positive tested dyads, but no significant effects on depressive and anxiety symptoms [26]. Similar results were found in a study on disclosing apolipoprotein E (APOE) genotypes and communicating AD risk to individuals with MCI and their study partners [29]. Systematic reviews on the current body of literature on the effects of AD biomarker disclosure on cognitively healthy and cognitively impaired individuals revealed that empirical data is sparse, with the majority of data based on studies regarding the disclosure of APOE genotype [30 –32]. The authors emphasize the need for more research on the impact of AD biomarker disclosure on psychological, behavioral, and social outcomes.

Overall, first findings indicate that disclosure of AD biomarker results has no major short-term harm on mental health when conveyed in a standardized manner and with follow-up support. Although theoretical considerations and empirical data from past and ongoing studies regarding the clinical utility of AD biomarker results disclosure to individuals in pre-dementia and dementia stages have been published, the effects on quality of life (QoL) have not been addressed in a comprehensive way. Hereby, QoL is an ethically important point of reference for medical care, especially in view of a health situation that can hardly be influenced. QoL can be defined differently; we refer to it in a broad understanding that includes the person and their environment as well as subjective and objective aspects as described within the Challenges and Potentials (CHAPO) Model of Quality of Life in the old age [33]. As such, continuative research on the impact of diagnostic labelling in at-risk individuals for AD dementia on QoL is limited. Research on the impact of subjective knowledge and awareness of AD diagnosis on QoL in individuals with MCI and mild AD dementia revealed that individuals that were aware of their diagnosis and prognosis had lower QoL than those that were unaware [34]. These findings were confirmed by a study on QoL of individuals with SCD and MCI, where reduced QoL in both groups compared to controls were reported [35]. In contrast, in a study on the relationship between APOE4 carrier status and QoL in cognitively healthy individuals no significant difference between APOE4 carriers and APOE4 non-carriers with regard to QoL were seen [36]. Hence, findings on QoL in the field of pre-dementia stages of AD are mixed and further research regarding the association of AD-biomarker status and QoL is needed.

Risk prediction offers opportunities for patients, in terms of early disease management or adapted life planning, to promote QoL, but given the natural progression of AD, knowledge of a high individual risk for developing dementia can also be severely burdening [37 –40]. Due to the limited therapeutic options and the absence of disease-modifying treatments, early AD detection and risk prediction of developing AD dementia might cause particular psychosocial distress, and might impact on the QoL of patients and their social environment [38]. Furthermore, the therapeutic options in pre-dementia stages, may hinder individuals at risk for AD dementia to judge on the potential benefits of AD-biomarker assessment. Most of these potential benefits are relative and strongly associated with the individual attitudes, beliefs, and expectations, personal resources and perceived role, QoL and spirituality, but also with social environment and support. Considering the above mentioned factors, counselling on AD detection and dementia risk prediction is a complex process and may lead to considerable heterogeneity and insecurity among clinicians, which stresses out the importance of guidance and standardization of disclosure practices [41]. At present, procedures of counselling and risk disclosure as well as an ethical and legal normative framework are not well developed [39 , 43]. Standardized and ethically reflected information procedures provided by professionals and longitudinal studies on patients’ and close others’ experiences and effects on QoL are needed [44].

This gap is addressed by the PreDADQoL study (Ethical and legal framework for predictive diagnosis of AD dementia: Quality of life of individuals at risk and their close others). In this study, the effects of biomarker-based dementia risk prediction in MCI-patients and close others with regard to QoL, mental health, behavioral and psychosocial outcomes, risk perception and expectations toward predictive AD diagnostics will be investigated. Finally, empirically informed normative (ethical and legal) considerations such as a respective framework will be formulated and a clinical guidance for counselling and disclosure in the context of predictive AD diagnostics will be developed. In order to meet these goals, the interdisciplinary study team consists of experts within the fields of ethics, law, clinical neurology, psychiatry and linguistics.

MATERIALS AND METHODS

The PreDADQoL study is a prospective transnational observational study with the aims: 1) to provide empirical data on the expectations and attitudes toward AD biomarker-based dementia risk estimation and the effects of such actions on mental health and QoL of the participants, 2) to develop an ethical and legal framework for AD biomarker-based dementia risk estimation in subjects with MCI and their close others, and 3) to provide on the basis of (1) and (2) a guideline for counselling, disclosure, and clinical management for MCI patients with regard to AD biomarker application and risk prediction. To allow a transnational comparability, the research is conducted in parallel in Spain and Germany.

Work package 1: Ethical approach

The aim of the ethical analysis of the PreDADQoL project is to develop an ethical framework, which together with legal and empirical aspects, informs the development of guidelines for the counselling of patients and close others. The ethical subproject is involved in defining the theoretical study concept, as well as the selection and the development of the questionnaires on attitudes, expectations, and different aspects of QoL according to a broad concept of QoL in line with the CHAPO-model as a multidimensional construct [33, 45]. This broad concept takes into account subjective and objective evaluation of environmental and individual factors, changes in life and results of life such as the concept of a successful life conduct.

To understand patients’ and their close others‘ attitudes and expectations is ethically of particular importance. Unrealistic expectations (e.g., because of a lack of understanding, misunderstandings, or wanting to hold on to a hope for cure) might intrude the capability for autonomous decision-making.

Preliminary data from patient interviews also suggest that some patients repress to think about the consequences of AD prediction which affects the validity of informed consent in predictive testing [46]. The repression to think about possible consequences may have several reasons, such as fears or a certain type of coping style.

From an ethical point of view, during the decision-making process the impact of QoL on patients and their close others should be an important part of the counselling process. In order to evaluate the individual benefit or harm during a predictive diagnostic procedure, health professionals need to understand the patients’ and their close others’ attitudes, expectations, fears, and beliefs well enough. In the literature, possible effects of dementia risk disclosure on QoL include matters of identity, self- and external stigmatization, depressive reactions, (disproportionate) changes in life planning, and the “pre-caregiver” status of close others [22 , 48]. Furthermore, the possibility of arising suicidal thoughts in patients receiving dementia risk information or dementia diagnosis should be kept in mind [40 , 49].

Issues related to the understanding of risk, the communication of risk [50], the enabling of self-determination and informed consent [51], or the implications of self-awareness of being already ill (“healthy ill”) [47, 52] are particularly ethically significant.

Regarding the close others, several ethically important aspects arise, such as being engaged much earlier, in the pre-dementia stages of the disease (pre-caregiver identity). In the field of early AD detection, close others also become important study partners in (prevention) trials, which means additional effort and dealing with study tasks. Eventually, the immense contribution of close others in providing informal or unpaid care to individuals with MCI and AD dementia and the imposed psychological and physical strain of caregiving should be kept in mind as well [48]. Therefore, the perspective of close others and their experiences and demands need to be addressed within counselling guidance.

There are important studies on counselling and disclosing genetic test results, e.g., the REVEAL study [29 , 54]; however, findings and approaches might not be applicable to dementia risk prediction by other means than genetic analysis. With regard to CSF- or PET-based AD detection, the literature provides some valuable contributions for counselling and disclosure processes and participants‘ comprehension of results [18 , 21]. In this regard, the novelty of the PreDADQoL project is the consideration of QoL and ethical and legal implications. Based on the analysis of ethical challenges in risk prediction against the background of fundamental moral rights and freedoms as dignity, freedom and self-determination, physical and psychological integrity, privacy, justice, and solidarity, an ethical and legal framework for predictive AD testing will be developed [55]. The analysis and evaluation of qualitative interviews with patients and their close others will provide empirical information about expectations, wishes, preferences and underlying assumptions as well as effects on QoL, that will inform the ethical and legal framework.

Work package 2: Legal approach

While there have been a number of treatises ad-dressing the legal and social implications of bio-marker-based prediction of AD dementia, and its disclosure internationally for quite some time (in general [39 , 56–59] and beyond legal aspects with a patient-oriented approach [18 , 60]), these mostly either remain on an abstract level, and especially for Roman Law countries like Germany and Spain, a number of unanswered questions remain. In particular, there is no specific framework regarding the legal aspects of informed consent, counselling of longer-term effects, and other particularities specific to this type of predictive testing. In this study, we therefore include an analysis of the legal framework, focusing on Spain and Germany as the study’s bases. While the two countries are exemplary in certain aspects, e.g., regarding general rules on information and consent, data protection, and anti-discrimination, the comparison also allows us to, in connection with the empirical findings, pinpoint cultural differences and their reflection in the law, e.g., regarding roles of caregivers and families, views to data sharing, and expectations of health systems.

First and foremost, the existing rules on when and how information must be given to a patient to obtain his or her consent to treatment and stipulate the prerequisites of a valid consent, currently do not entirely prescribe the scope and extent of information about predictive treatments as well as psychosocial implications, and about the disclosure of risks. While the right to self-determination endows every patient with the fundamental freedom to accept or reject all treatment, including diagnosis and early diagnostics, the according role of the physician as a specialist is to communicate the knowledge needed by the patient concerning all integral factors of the decision whether to accept treatment and diagnosis, to decide upon possible alternatives, or to reject treatment altogether (cf., regarding Germany, section 630d (1) and (3) of the German Civil Code [BGB], and regarding Spain, the Spanish Law 41/2002). Since the consequences imposed by prediction of AD dementia may have a severe impact on the private life of the patient, and may, with still a relatively high margin of error, not even be correct, counselling of the patient including psychosocial aspects in case of a positive finding may be needed beyond mere medical information. To this day, however, it remains unclear how such counselling is to be incorporated into the existing legal standards for informing the patient. Notwithstanding some rules on counselling for genetic testing, no specific standards for predictive counselling by physicians or others have been prescribed so far in Spain or Germany, leaving this duty in its vagueness with the physician. In this project, the empirical and ethical work packages will therefore be assessing what factors are particularly important for patients in making their treatment decision, and what the most relevant pieces of information are that consequently must be included in treatment information and should be included in any counselling. Accordingly, the question of liability for adverse impacts of a decision made by the patient on the grounds of a specific counselling remains unanswered. Also, the role of close others within the legal concept of information and consent is of high practical importance. As a general rule, the patient alone is the one to make the treatment decision, and any findings about detected diseases or risks is to be communicated only to the patient and to no one else, including close relatives or others who can be largely impacted by such a finding as well. With the increase of methods of prediction of a chance for later diseases, potentially bringing a large social and psychological burden for the individual patient and his/her close social surroundings, the inclusion of significant others as early as in the decision of whether or not to undergo predictive diagnostics in the first place, must be taken into account, at least by making the patient aware of the impact of his/her surroundings by counselling.

Secondly, concerning data protection and anti-discrimination law, biomarker test results are highly sensitive, and can easily be used for discriminatory practices, albeit generally not covered by the higher protection level for genetic predictive information. In regard to social laws and the existing Health Care schemes, predictive methods have yet to be located and integrated into the systems (cf. also, for a Common Law perspective [56]), which are mainly still primarily aimed at curative instead of predictive needs.

Thirdly, the rising number of new possibilities to predict risks for a later development of a disease in a person on the grounds of biomarkers and increasingly individualized factors, require constant adjustment and assessment of the legal requirements for storing, sharing, safeguarding, and using the data necessary for an optimized analysis and prediction. Also, the regulation of access to such stored information as well as disclosure rights and duties of patients are still somewhat unclear: In most European countries the use of genetic information is specifically regulated and mostly prohibits the use of such information or a duty to disclose it in regard to employment contracts and insurance policies. This especially applies to all parties of the Oviedo Convention, (cf. Convention on Human Rights [61]). However, since Germany has not signed nor ratified the Oviedo Convention, it may not have direct implications on Germany.

Apart from genetic information, the use of “mere” medical information is governed by very general rules on data protection, which do not usually ex-clude duties to inform private insurance companies and future employers about medical risks that have become disclosed on occasion of medical treatments, including early diagnoses. This study will also address this issue in the exemplary countries of Spain and Germany, especially since it has not been subject to scrutiny across the breadth of national anti-discrimination laws in Europe (internationally, cf. [59, 62] for the legal rules across U.S. states, and for DTC genetics in Europe, cf. [63, 64]).

The more advanced the possibilities to predict later manifestations of diseases become, the more probable is an ensuing economic and social discrimination of persons carrying medical risks [65]. It seems desirable that at least these direct social implications of undergoing predictive testing should be made part of the information process to ensure that the patient can duly weigh risks and chances beyond the medical aspects.

For these reasons, a framework will be developed in this project by combining the ethical approach with a dedicated legal analysis laying out and assessing the fundamental legal prerequisites hitherto not specifically applied to predictive AD-biomarker testing. These findings will be incorporated into the development of an ethically and legally sound and safe framework for informing and counselling the patient as well as disclosing individual risks and its implications for the social life and well-being, and the life planning of the patients and their close others.

Work package 3: Empirical study

Study population

Within the empirical study, MCI patients and their close others are recruited from memory clinics in Barcelona (Fundació ACE), Spain, and Cologne (Center for Memory Disorders, Department of Psychiatry, Department of Neurology, University Hospital of Cologne), Germany. At each site 50 MCI-patients and 50 close others are enrolled (total number of participants 200). MCI-patients who went through the routine diagnostic work-up including neuropsychological testing (CERAD [66] and NBACE [67]), cerebral magnetic resonance imaging (MRI) and blood test are potentially eligible for the PreDADQoL study.

The NIA-AA criteria for MCI [3] are applied and operationalized by a performance ≤-1.5 standard deviation in at least one episodic memory test. Additional inclusion criteria are: age ≥55 years, lack of contraindication for lumbar puncture, and a reliable close other. The anticipated close other should be in contact regularly with the patient and would be able to accompany the patient to all study visits and able to contribute to the study. The close others need to perform ≥27 points in the Mini-Mental State Examination (MMSE) [68]. Severe depression [69], anxiety [70], and suicidality [71] are an exclusion criteria for all subjects. Furthermore, participants are assessed with the structured interview for DSM-IV Axis I Disorders [83] to rule out major or minor depressive episodes or a general anxiety disorder at screening. Detailed in- and exclusion criteria are listed in Table 1.

Table 1

Inclusion/Exclusion criteria for study participants

Inclusion criteria patients	Exclusion criteria patients
–Clinical criteria for amnestic MCI due to AD (according to criteria of NIA-AA [3]):	–Dementia.
–Performance of ≤-1.5 SD below the normative mean in one memory test.	–Evidence of non-AD neurodegenerative disorder: Parkinson’s disease, dementia with Lewy bodies, frontotemporal lobar degeneration, very rapid cognitive decline that occurs over weeks or months (typically indicative of prion disease, neoplasm or metabolic disorders).
–Single or multiple domain impairment.	–Brain tumor.
–Cognitive concern reflecting a change in cognition reported by patient or informant or clinician.	–Presence of extensive cerebrovascular disease on structural brain images, which is suggestive of vascular cognitive impairment.
–Preservation of independence in functional abilities.	–Clinical relevant depressive symptoms (GDS >11), clinical relevant anxiety symptoms (GAI >11) and suicidality.
–Written informed consent from patient prior to any study procedures. All patients must be able to give informed consent personally and have capacity for such consent.	–Illiteracy.
–Patients must have a reliable close other, who is in close contact with the patient and able to contribute to the questionnaires and rating scales at the study visits. This person must sign a separate informed consent form which describes their contributions during the study.	–Contraindication for lumbar puncture.
–Patients must have fluency in the test language.
–Age ≥55 years.
Inclusion criteria close others	Exclusion criteria close others
–MMSE ≥27.	–Dementia and/or MMSE ≤26.
–Written informed consent from patient prior to any study procedures. All patients must be able to give informed consent personally and have capacity for such consent.	–Clinical relevant depressive symptoms (GDS >11), clinical relevant anxiety symptoms (GAI >11) and suicidality.
–Close contact with the patient and able to contribute to the questionnaires and rating scales at the study visits.	–Illiteracy.
–Must have fluency in the test language.

MCI, mild cognitive impairment, NIA-AA; National Institute on Aging and Alzheimer’s Association; GDS, Geriatric Depression Scale; GAI, Geriatric Anxiety Inventory; MMSE, Mini-Mental State Examination.

Regulatory review and approval

The PreDADQoL study was approved by the local Ethics Committees of the Medical Faculty of the University of Cologne and the University Hospital of Cologne and the Hospital’s Clinic Ethical Committee Barcelona. The reference number is 17–016. Written informed consent is obtained from all study participants prior to participate in the study and the consent process is documented. Participants not being able to give a written informed consent are not enrolled in the study. Study participants are informed of all risks and protections and are able to withdraw from the study at any time for any reason. Potential risks might include psychological distress in the process of biomarker assessment and dementia risk prediction.

Study design

MCI patients and their close others enrolled in the study take part in a counselling session with a trained neurologist or psychiatrist, where information about MCI, AD, CSF biomarker risk prediction of AD dementia, and preventive measures are provided in a standardized and manual-guided procedure. Participants receive oral and written, including graphical, information and are offered handout material to take home. After the counselling session, MCI patients willing to undergo AD CSF biomarker testing receive an appointment for a lumbar puncture. To those patients and their close others, the biomarker results are communicated with the help of graphics and handouts in a subsequent risk disclosure session. The risk disclosure is performed by a trained neurologist or a psychiatrist and also follows a manual-guided procedure. MCI patients who do not wish to undergo biomarker testing proceed with the survey without lumbar puncture and risk disclosure. The effects of the procedures, including counselling, as well as disclosure of biomarkers and communication of dementia risk, on several outcomes are examined at three (Barcelona) to four (Cologne) different time points (baseline, one week, three months, and twelve months post-disclosure or post-decision against CSF testing). The flowchart of the study design is presented in Fig. 1.

Fig. 1

Study flowchart. MCI, mild cognitive impairment; CSF, cerebrospinal fluid; +CSF, MCI patients consented to lumbar puncture/biomarker assessment; - CSF, MCI patients not consented to lumbar puncture/biomarker assessment.

Counselling and risk disclosure

During the counselling and risk disclosure sessions biomarker-based risk estimates based on the current evidence of research are communicated to the MCI patients and their close others. Biomarker-based risk estimates for developing AD dementia within 5 years after the MCI diagnosis are currently obtained from the meta-analysis by Vos et al. [7]. Overall risk estimation for developing AD dementia based on the clinical MCI diagnosis only (without AD biomarker use) are currently taken from the meta-analysis by Mitchell et al. [6, 72]. Information material on relevant issues was developed under consideration of the cognitive impairment of the participants and the challenge of providing complex probabilistic numerical risk information. For risk communication, oral, written and graphical (icon arrays, bars and line charts) information, including take-home material, was developed, guided by literature review on risk communication techniques [19 , 73–75]. The study protocol for the counselling and disclosure sessions is designed according to the previously published protocols and recommendations in this field [15 , 19]. Information material presented during the counselling and disclosure sessions includes information about MCI, AD, AD dementia, biomarker, risk prediction, risk factors, preventive and therapeutic options at the stage of MCI [3 , 76, 77].

Outcome measures

The empirical project uses a longitudinal mixed methods approach (quantitative instruments and qualitative interviews) to measure the expectations toward biomarker-based dementia risk prediction and the effects of early disease detection on various outcomes. The assessments take place at three (site Barcelona) to four (site Cologne) time points. At baseline, 3 months, and 12 months (12 months follow-up in Cologne, only) after risk disclosure or the decision against biomarker assessment a comprehensive set of questionnaires is completed with all subjects (Table 2). An additional short visit (on-site or by phone) is performed one week post-disclosure or post-decision against biomarker assessment, respectively, in order to assess depression and anxiety on short-term follow-up. The quantitative assessment battery includes validated [69–71 , 78–84] and newly developed questionnaires (see sections “Expectations toward biomarker-based estimation of dementia risk”, “Risk communication”, and “Health behavior changes”). In Cologne, a subgroup of 15 dyads are additionally interviewed at baseline and 3 months follow-up by a trained linguist.

Table 2

PreDADQoL study schedule

	Screening and enrollment	BASELINE	LP (optional)	VISIT 0 Disclosure of CSF biomarker result (optional)	VISIT 1	VISIT 2	VISIT 3 (only Cologne)
Timepoints:
MCI patients with LP and their close others	0	7 days	4 weeks	6 weeks	7 days	3 months	12 months
		(±3 d)	(±7 d)	(±7 d)	(+7/–3 d)	(±7 d) 0	(±14 d)
					post visit 0	post visit 0	post visit 0
MCI patients without LP and their close others	0	7 days			7 days	3 months	12 months
		(±3 d)	(+7/–3 d)	(±7 d)	(±14 d)
					post baseline	post baseline	post baseline
Enrollment:
Eligibility screen	X
Informed consent	X
Allocation	X
Interventions:
Counselling	X
LP (optional)			X
Disclosure of CSF biomarker				X
results (optional)
Assessments:
Interviews (only Cologne)		X				X
Expectations		X				X	X
Quality of life
1. WHO-QoL BREF [79]		X				X	X
2. Spirituality [86]		X				X	X
3. Satisfaction with life [80, 81]		X				X	X
4. Affective well-being [87]		X				X	X
Risk communication
1. Numeracy [74]		X
2. Risk perception		X				X	X
3. Risk recall		X				X	X
4. Coping strategies [82]		X
Mental health
1. Depression [69]	X				X	X	X
2. Anxiety [70]	X				X	X	X
3. Suicidality [71]	X					X	X
Behavioral change
1. Lifestyle		X				X	X
2. Advance directives	X					X	X
3. Insurance purchase						X	X
4. Health resource utilization [84]	X					X	X

CSF, cerebrospinal fluid; LP, lumbar puncture; MCI, mild cognitive impairment.

Expectations toward biomarker-based estimation of dementia risk

According to our literature search expectations can be directed to different entities such as persons, actions, objects, organisms, social groups/institutions, events or states/characteristics and are highly thematically specific. This diverse spectrum of expectations led to the necessity of developing a new questionnaire specifically to measure the expectations of individuals with MCI and their caregivers toward biomarker-based AD detection and dementia risk prediction. The questionnaire was designed based on a systematic literature search and a qualitative pilot-study. For more detailed description on the development see sections “Results: Pilot study” and “Results: Development of the new questionnaire on expectations toward biomarker-based estimation of dementia risk”.

Quality of life

Research on QoL in individuals with MCI is sparse and mostly inconsistent [85]. A recent publication from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) revealed that individuals with MCI show lower QoL with regard to autonomy [85]. Furthermore, understanding the impact of applying early AD diagnostic procedures on QoL in individuals with MCI is of major importance, when counselling patients and their close others about predictive AD diagnostic work-up, as the awareness of the risk state for AD dementia may lower QoL [34]. Therefore, monitoring QoL in the diagnostic work-up of AD and clinical follow-up may be useful to detect changes in general wellbeing and mood to enable a tailored and holistic clinical management.

In order to encompass a broad concept of QoL in the selection of QoL questionnaires, we were guided by the challenges and potentials (CHAPO) [33] of a multidimensional framework of QoL, which differentiates between an individuals’ internal value system, resources, and competencies on the one hand, and external (societal) value systems, conditions, and opportunity structures on the other. This means it takes into account the resources and aims of the individual, offering a framework for evaluation and explanation of variabilities in qualities of life, including a normative perspective and the dimension of a meaningful life. For PreDADQoL these considerations led to the selection of the WHOQoL-Bref [79], the questionnaire on satisfaction with life (FLZM) [81], the satisfaction with life scale [80], the questionnaire on spirituality [86], and the positive and negative affect schedule (PANAS) [87]. In order to reconstruct the individual understanding of QoL to which MCI patients and their close others refer, the results of these questionnaires will be evaluated under consideration of the findings of the qualitative survey.

Mental health

A major concern in the early detection of AD and the risk prediction of developing AD dementia within the near future are psychological side effects of the disclosure. Given the fact that AD is a progressive neurodegenerative incurable disease, patients and their social environment might face severe psychological distress. Therefore, this study investigates depression [69], anxiety [70], and suicidality [71] at screening and follow-up visits (Table 2).

Risk communication

Research in the field of early AD diagnosis sug-gests that individuals at risk for AD dementia specifically ask for a definite diagnosis and wish to clarify their health status [19 , 53]. Informed decision-making in health-related matters includes numerical literacy, which encompasses comprehension of quantitative measures, probabilities, risk, and proportions [88]. Conveying complex AD biomarker-based risk information is a major challenge when facing cognitively-impaired individuals and their caregivers, and furthermore, little is known on how these individuals handle health-related risk information [89]. To investigate this topic, we employ several questionnaires. Firstly, to measure the general level of numeracy in MCI patients and their close others, questionnaires regarding the subjective and objective numeracy [74] are employed at baseline. Secondly, in order to measure the individual risk perception of developing AD dementia, all participants receive questionnaires at baseline, 3 months follow-up, and 12 months follow-up (12 months follow-up in Cologne, only) at which time points their subjective appraisal of the individual risk of developing AD dementia is addressed. Additionally, all participants receive a questionnaire regarding the risk recall, where the communicated risk of developing AD dementia is requested. These questionnaires were newly developed, following templates from studies on genetic risks [90, 91], and tested during the pilot-study phase. Within the mixed methods approach of the main study, risk perception is assessed from the quantitative and qualitative perspective.

Health behavior changes

Health behavior changes as a result of AD risk disclosure are described in the literature [22 , 92–96]. This study looks at complex behavioral changes such as health resource utilization [84], modification of lifestyle, insurance-purchase, and determination of advance directives. For the three latter topics, a new questionnaire is applied, which was developed for the purpose of this study and has been tested in the pilot-study phase.

Coping strategies

Coping strategies, like assimilative and accommodative coping, might change during the life course. In uncontrollable circumstances, as in the case for the diagnosis of AD, flexible coping mechanisms can significantly decrease psychological distress. To measure tenacity and flexibility, we employ the short version of the Flex-Ten scale [82].

Qualitative interviews

As mentioned above, in addition to the question-naires, in Cologne 15 dyads are interviewed qualitatively at baseline and 3 months follow-up visit. MCI patients and close others are interviewed separately. The interviews are semi-structured, i.e., they contain narrative passages based on open questions. In the baseline interview, the questions concern the history of the cognitive impairment up to the current situation, the information and decision-making phase on the biomarker application as well as expectations and possible future conceptions (expectations and attitudes) in relation to the biomarker-based risk estimation. In the follow-up visit, the questions address the period post-disclosure or post-decision against the biomarker assessment. Furthermore, the consequences and effects of the biomarker assessment or the decision against the procedure, respectively, as well as possible future conceptions (effects of dementia risk prediction on QoL) are brought up.

Data analysis

The PreDADQoL study pursues a longitudinal mixed methods design. The quantitative data will be surveyed with validated as well as newly developed questionnaires and analyzed in an exploratory fashion using standard statistical approaches, including descriptive analyses and pre-post comparisons. The explorative data analysis is performed to generate hypotheses that will eventually provide a rationale to perform further studies on this matter and assess implementation in clinical practice. Therefore, a sample size justification is not needed. Descriptive statistics will be used to characterize the sample in terms of its demographics and baseline characteristics using independent-sample t-test or chi-square tests, respectively. Group comparisons for evaluating differences between groups (patients versus close others, CSF+ versus CSF-, Spanish cohort versus German cohort) on the outcomes will be performed. To examine the changes over time between groups a multivariate repeated measure analysis (general linear model) will be conducted. Study data is collected, pseudonymized, and managed using REDCap® (Research Electronic Data Capture) electronic data capture tools hosted at the Clinical Trials Centre Cologne, Germany.

For the qualitative approach, episodic interviews are applied [97, 98]. The main aim of episodic interviews is to distinguish episodic/narrative and semantic knowledge. The episodic knowledge of the participants is explored based on questions that encourage narrating subjective perceptions of certain situations and feelings. The semantic knowledge is explored by asking questions about certain central terms and terms used by the interviewed persons (e.g., the understanding of happiness, contentment, satisfaction, risk or QoL, etc.). The interviews will be evaluated using conversational linguistic methods [99], including particularly the analysis of thematic and semantic aspects.

The empirical approach of the project can thus be described as a mixed methods approach [100, 101], with regard to two essential aspects: Firstly, the quantitative study part was preceded and thereby supported by a preliminary qualitative phase. This pilot-study procedure was inductive and explorative. The pilot-study contributed to the development of new instruments (see sections “Expectations toward biomarker-based estimation of dementia risk”, “Risk communication”, and “Health behavior changes”). Secondly, substantial aspects of the main longitudinal study are carried out quantitatively and qualitatively in parallel. Thus, essential topics of the study are examined simultaneously from a quantitative and qualitative perspective at two different time points. This type of mixed methods approach not only allows data to be compared, but also enables quantitative results to be interpreted with the assistance of qualitative results and vice versa.

RESULTS

Pilot study

We conducted a biphasic pilot-study in order to develop the interview guideline and the questionnaires on expectations and the fulfilment of expectations toward biomarker-based estimation of dementia risk (see sections “Expectations toward biomarker-based estimation of dementia risk” and “Qualitative Interviews”). Furthermore, the pilot study served as a test phase to revise the newly developed questionnaires regarding risk recall, risk perception and lifestyle changes (see sections “Risk communication” and “Health behavior changes”), and the questionnaires on expectations and the fulfilment of expectations (see section “Expectations toward biomarker-based estimation of dementia risk”), respectively. A total of 12 MCI patients and 10 close others from the Center for Memory Disorders at the University Hospital of Cologne were recruited. Findings from the interviews were consecutively taken into consideration when developing the standardized protocol for the counselling and risk disclosure sessions (see section Counselling and risk disclosure).

Development of the new questionnaire on expectations toward biomarker-based estimation of dementia risk

To measure the expectations of individuals with MCI and their caregivers with regard to biomarker-based AD detection and dementia risk prediction, a new questionnaire was developed. First, a systematic search was conducted in three literature databases (PubMed, LIVIVO, Electronic Journals Library (Elektronische Zeitschriftenbibliothek, EZB)). The search for existing full-text publications on questionnaires regarding “expectations“ on the basis of a broad search term (“expectation^* [Title] AND questionnaire”) yielded around 550 search results. We did not restrict the search terms to a specific disease entity (e.g., AD) in order to capture the current body of literature regarding questionnaires on expectations. After screening process, ten publications were included that could support the purpose of our study. The existing health-related questionnaires on “expectations” are geared toward people (certain occupational groups, people in social relationships with the respondents, etc.) and institutions (e.g., companies, daycare centers) or longer processes/relationships (e.g., care relationship, doctor-patient relationship) [102]. However, these focus especially on treatments that lead to cure (e.g., rehabilitation) and are therefore not suitable for the transfer to the topic of predictive biomarker diagnostics of AD.

With regard to the literature on various predictive investigations, there are mainly qualitative surveys on reasons, ideas about advantages and disadvantages, as well as fears associated with the (expected) illness [103]. Among the literature findings, mainly studies regarding the reasons in favor or against biomarker application in the pre-dementia stages of AD were carried out [20 , 104]. Predictive tests for other diseases and genetic predictive testing were judged as suitable to support the development of a questionnaire concerning subjective expectations toward prediction of AD dementia [105, 106]. However, aspects and items relating to expectations in the context of genetic heredity were not compatible.

Overall, the data analysis revealed two main findings: 1) The spectrum of expectations toward different entities addressed by the questionnaires is highly diverse and thematically specific. 2) Since biomarker-based dementia risk estimation can be conceptualized as an action, specific questionnaires for our purpose need to consider expectations “toward an action or possible medical examination”, specifically in the field of AD detection and dementia risk prediction.

In addition to the literature search, we used the qualitative pilot-study for the development of the new questionnaire. Within the qualitative pilot study, MCI patients and close others were asked for their expectations toward the early pre-dementia AD diagnoses and biomarker-based dementia risk estimation. The results were analyzed and clustered by content analysis.

Both approaches together resulted in three main domains, of which a questionnaire was composed to explore subjective expectations toward prediction of AD dementia as well as follow-up questionnaires concerning the fulfilment of those expectations: 1) Expectations concerning changes (regarding the future, feelings and acting), 2) expectations concerning the AD biomarker test results, and 3) expectations regarding the consequences of the AD biomarker test results and diagnosis, including possible fears and worries. Together they build a concept of “expectations regarding an event (predictive medical intervention)”. PreDADQoL is the first study to our knowledge that systematically examines expectations toward AD biomarker-based estimation of dementia risk qualitatively and quantitatively with a newly developed tool.

For the longitudinal main study, three different questionnaires were compiled: one concerning expectations toward the biomarker-based dementia risk estimation for the baseline visit (before the potential CSF sample collection and biomarker assessment), and two questionnaires for the 3 months and 12 months follow-up, respectively, concerning the fulfilment of the expectations as well as changes in the decision for, or against the biomarker-based AD detection and dementia risk prediction.

DISCUSSION

Due to advances in the field of biomarker research in AD, early diagnosis of AD and prediction of dementia based on biomarkers are moving from a research topic into clinical practice. This development will be even accelerated, once disease modifying drugs are available. While biomarker technologies are rapidly evolving, the required ethical and legal framework of such actions as well as adequate concepts and materials for patient counselling, are only recently under development. Clinical and research data support that patients and their close others wish clarity and further medical information about the cause and prognosis of the memory complaints [20 , 26]. Hence, there are important ethical considerations to ensure that appropriate counselling and information is implemented when offering biomarker-based early AD detection [39 , 43]. The PreDADQoL study is currently ongoing, with the recruitment phase not being completed yet. To the best of our knowledge, this is the first study to address the expectations and QoL in individuals with MCI and their close others in the context of biomarker-based detection of AD with a mixed method approach. Research on clinical and ethical implications in early diagnosis of AD is focused on effects of these diagnostic procedures on patients, but little is known about the expectations and attitudes prior to predictive AD diagnosis and the effects on QoL in individuals with increased dementia risk and their close others [20 , 31]. The PreDADQoL project is a comprehensive binational project with ethical, legal, and empirical components and will substantially contribute to improve medical practice in the field of biomarker-based dementia risk estimation. Finally, the study will provide an extended amount of quantitative and qualitative data, which will encourage more research, including long-term follow-up of patients, who received individual dementia risk estimates.

Trial status

This is protocol version 4.0 (30.07.2019). This study is registered in the German clinical trials register (Deutsches Register Klinischer Studien, DRKS): http://www.drks.de/DRKS00011155, DRKS registration number: DRKS00011155, date of registration: 18.08.2017. Patient recruitment began in June 2018 and is expected to be completed by the end of May 2021. The study procedures are expected to be completed by the end of August 2022.

Footnotes

ACKNOWLEDGMENTS

The authors wish to thank Jennifer H. Lingler for support regarding the protocol of the counselling and risk disclosure sessions.

This work was supported by the Federal Ministry of Education and Research –BMBF as part of the Network of European Funding for Neuroscience Research –ERA-NET NEURON (“Ethical and Legal Framework for Predictive Diagnosis of Alzheimer’s Dementia: Quality of Life of Individuals at Risk and their Close Others” (PreDADQoL); funding number: 01GP1624). This joint project is conducted under the leadership of the Cologne Center for Ethics, Rights, Economics, and Social Sciences of Health (ceres). The sponsor did not have any influence on study initiation, conducting and reporting.

Authors’ disclosures available online ().

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