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Biomarker-Based Risk Prediction of Alzheimer’s Disease Dementia in Mild Cognitive Impairment: Psychosocial, Ethical, and Legal Aspects. Study Protocol of the PreDADQoL Project



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.
Journal of Alzheimer’s Disease 80 (2021) 601–617
DOI 10.3233/JAD-200484
IOS Press
Biomarker-Based Risk Prediction of Alzheimer’s Disease
Dementia in Mild Cognitive Impairment: Psychosocial,
Ethical, and Legal Aspects
Study Protocol of the PreDADQoL Project
Ayda Rostamzadeha,1,, Carolin Schweglerb,1, Silvia Gil-Navarroc, Maitée Rosende-Rocac, Vanessa Romotzkyb, Gemma Ortegac, Pilar
Canabatec, Mariola Morenoc, Björn Schmitz-Luhnb, Mercè Boadac,d, Frank Jessena,e,f and Christiane Woopenb,g
aDepartment of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
bCologne Center for Ethics, Rights, Economics, and Social Sciences of Health (ceres), University of Cologne, Cologne, Germany
cResearch Center and Memory Clinic, Fundaci´o ACE, Institut Catal`a de Neuroci`encies Aplicades, Universitat Internacional de Catalunya,
Barcelona, Spain
dNetworking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
eGerman Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1, Bonn, Germany
fExcellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
gInstitute for the History of Medicine and Medical Ethics, Research Unit Ethics, University of Cologne, Faculty of Medicine and University
Hospital Cologne, Cologne, Germany
1These authors contributed equally to this work
*Corresponding Author
ACCEPTED VERSION (30 December 2020), Pre-press 4 February 2021
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
{pp. 602 of the final paper} 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 expressed as aggregated extracellular amyloid-ß42
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 [35].
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 [812]. 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 [1519]. 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 [2027]. 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].
{pp. 603} 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 [3032]. 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 [3740]. 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, 42,
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
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.
{pp. 604}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,
40, 47, 48]. Furthermore, the possibility of arising suicidal thoughts in patients receiving
dementia risk information or dementia diagnosis should be kept in mind [40, 44, 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, 53, 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, 19, 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 {pp. 605} 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 addressing the legal and social implications of
biomarker-based prediction of AD dementia, and its disclosure internationally for quite some
time (in general [39, 5659] and beyond legal aspects with a patient-oriented approach [18, 32,
42, 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 {pp. 606} 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 exclude 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 (Fundacio 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 {tab. 1 fin. on pp. 607}.
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 17016. 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, {pp. 607}
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.
Figure 1) Study owchart. MCI, mild
cognitive impairment; CSF, cerebrospinal
uid; +CSF, MCI patients consented to
lumbar puncture/biomarker assessment; -CSF,
MCI patients not consented to lumbar
puncture/biomarker assessment.
{fig. 1 fin. on pp. 608}
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, 7375]. The study protocol for the counselling and disclosure
sessions is designed according to the previously published protocols and recommendations in
this field [15, 18, 19]. Information material presented during the counselling and disclosure
sessions includes information about MCI, AD, AD dementia, biomarker, risk prediction, risk
factors, preventive {pp. 608} and therapeutic options at the stage of MCI [3, 5, 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). {tab. 2 fin. on pp. 609}
An additional short visit (onsite 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 [6971, 74,
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.
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 {pp. 609} 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, {pp. 610} 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 suggests that individuals at risk for AD dementia
specifically ask for a definite diagnosis and wish to clarify their health status [19, 20, 24, 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, 24,
9296]. 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 questionnaires, 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 {pp. 611} 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.
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 {pp. 612} application in the pre-dementia stages of AD were
carried out [20, 26, 103, 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.
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, 25, 26]. Hence, there are important ethical considerations to ensure that
appropriate counselling and information is implemented when offering biomarker-based early
AD detection [39, 40, 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, 24, 26, 30, 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):,
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.
{pp. 613} 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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... Weitere inhaltsbezogene Herausforderungen sind u. a. das generelle Verständnis von Wahrscheinlichkeiten, das Antizipieren der Auswirkungen von Risikowissen auf die Lebensqualität und das Wohlbefinden, die emotionale, soziale und rechtliche Situation sowie die Frage, ob von Betroffenen verstanden wird, dass die Prädiktion nur ein Risikowissen vermitteln kann und keine Diagnose oder Therapie darstellt (Schmitz-Luhn et al. 2019;Rostamzadeh et al. 2021). ...
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Wissen ist ein zentraler Baustein von Gesundheitskompetenz. Wissen wird in medizinisch-beratenden Kontexten oft im Sinne von Informationen verstanden, die unidirektional vermittelt und auf Patient*innenseite behalten werden müssen. Angemessene und optimal aufbereitete Informationen sind aber nur eine von diversen Gelingensbedingungen von Gesprächen – interaktive Komponenten und Vorwissen spielen ebenfalls eine wichtige Rolle. Für die Verbesserung von Beratungsgesprächen zur Risikoprädiktion der Alzheimer-Demenz lohnt sich ein Blick auf Wissensquellen, die Patient*innen und Angehörige explizit angeben oder mittels sprachlicher Positionierungen in Gesprächen als Träger*innen epistemischer Autorität auszeichnen. Im Beitrag werden Wissensbestände und -quellen untersucht, die aus Interviewdaten der PreDADQoL-Studie herausgearbeitet wurden. Folgende übergeordnete Kategorien sind im Text differenziert und erläutert: (1) der (ehemalige) medizinnahe berufliche Hintergrund, (2) Demenzerkrankungen im sozialen Umfeld, (3) weitere Krankheitserfahrungen, (4) unbestimmtes (Allgemein-)Wissen und (5) die (mediale) Öffentlichkeit. Es finden sich verschiedene relevante Typen von Wissensbeständen, z. B. (erstpersonales) Erfahrungswissen, Sprachwissen, prozedurales Wissen sowie (vages) Alltags- und Weltwissen, die jeweils zu unterschiedlichen Empfehlungen für die Praxis führen. Die Ergebnisse verdeutlichen, dass nicht-ärztliche Wissensquellen bei gesundheitsbezogenen Entscheidungen bedeutsam sind. Sie sollten eingehender beforscht werden und können Beratungsgespräche zur Prädiktion bereichern.
... In Alzheimer's disease (AD) especially, research and debate on the ethical aspects of risk disclosure is some way ahead, which opens up the possibility of learning from a comparable situation in which some guidelines already exist, [1][2][3]28 although internationally accepted recommendations based on stakeholder involvement and empirical data are still in progress. 29,30 In the first instance, ethical debates on risk disclosure in AD have revealed the necessity of a differentiation between the various states of prognostic certainty. For the preclinical phase of AD, in which individuals do not experience any neuropsychological symptoms, it is known that some individuals with a biomarker constellation suggestive for AD will never develop AD during their lifetime, making it particularly important to consider the potential harms of risk disclosure, especially as this state is mostly diagnosed within clinical studies. ...
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Background: Impressive progress in the understanding of the prodromal phase of Parkinson's disease (PD) in recent years has enabled the generation of disease prediction models. However, a remaining diagnostic uncertainty and lack of therapeutic options for affected individuals has resulted in a variety of ethical issues that have not to date been addressed sufficiently. Moreover, differences in the specificity of prodromal symptoms and possible subtypes of PD, especially the presence of rapid eye movement (REM) sleep behavior disorder (RBD), may have an important impact on prognostic counseling. Objectives: To derive a guideline for risk disclosure in prodromal PD based on the current literature and expert opinion. Methods: We performed (1) a literature review on prognostic counseling in PD and (2) consulted with international experts on prodromal PD using a semi-structured questionnaire based on a Delphi approach to evaluate recommendations for risk disclosure in PD. Results: The literature research revealed only 11 publications addressing prognostic counseling, with only two studies directly addressing affected individuals and most studies focusing on risk disclosure in RBD. The expert survey revealed the importance of distinguishing between individuals with and without RBD in prognostic counseling. Conclusions: Based on the current literature and expert recommendations, a guideline for risk disclosure in prodromal PD for clinical care and research could be elaborated. Prognostic counseling should include differentiation between individuals with and without RBD, taking into account the high uncertainty of risk calculation in RBD-negative prodromal PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Progress in predictive medicine has increased the challenges to navigating complex risk information for patients and healthcare professionals. This contribution investigates how people facing the risk of developing Alzheimer’s dementia perceive risk, what aspects are relevant to their health literacy, and how to promote individual health literacy in predictive medicine. We conducted a qualitative study analyzing narrative interviews, body maps, and sociodemographic data from persons who had undergone early predictive procedures in a memory clinic. We understand the promotion of health literacy as an ethical task in predictive medicine and argue for (1) emphasizing personal resources to promote subjective health literacy, (2) reframing communication and decision-making about disease risk, and (3) teaching skills for value-sensitive, individualized risk communication.
Advances in biomarkers, genetics, and other data used as dementia risk evidence (DRE) are increasingly informing clinical diagnosis and management. The purpose of this Mini-Forum is to provide a solutions-based discussion of the ethical and legal gaps and practical questions about how to use and communicate these data. Investigators often use DRE in research. When participants ask for their personal results, investigators have concerns. Will data that was intended to study groups be valid for individuals? Will sharing data cause distress? Debates around sharing DRE became heated when blood-based amyloid tests and amyloid reducing drugs appeared poised to enable clinicians easily to identify people with elevated brain amyloid and reduce it with a drug. Such an approach would transform the traditional role of DRE from investigational to foundational; however, then the high costs, uncertain clinical benefits and risks of the therapy led to an urgent need for education to support clinical decision making. Further complicating DRE use are direct to consumer genetic testing and increasingly available biomarker testing. Withholding DRE becomes less feasible and public education around responsible use and understanding become vital. A critical answer to these legal and ethical issues is supporting education that clearly delineates known risks, benefits, and gaps in knowledge, and communication to promote understanding among researchers, clinicians, patients, and all stakeholders. This paper provides an overview and identifies general concepts and resource documents that support more informed discussions for individuals and interdisciplinary groups.
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Being confronted with health risks implies challenges to mental health and well-being, requiring persons to find a balance between threat and confidence. The ‘power of definition’ with respect to health risks predominantly lies with professionals, implying that there is one appropriate way of understanding and interpreting risk-related information. This chapter will invite for a reflection on the potential of qualitative research in re-claiming the power of definition, offering the opportunity for a co-construction of concepts such as risk, vulnerability, and mental health. The aim is to highlight the particular value of different methodological approaches for opening up definitional spaces between scientists and research participants. It is grounded in the assumption that persons faced with a health risk construct their personal narratives to find a meaningful way to manage their situation, embedded in their biographical and social context. Narrative interviews with persons faced with a mental health risk were analysed in a circular process using complementing methodological perspectives from two disciplines: ethnology and linguistics. The findings were situated within a sociology of knowledge framework, focusing on the power of definition concerning a person’s health and health risks. Herein, particular attention was drawn to ethical and methodological issues of assessing concepts such as ‘risk’ or ‘vulnerability’; and the importance of (self-)reflexivity in conducting research in this field. Methodological reflection on these issues may contribute to constructively dealing with the tension between a standardised biomedical conception and an open, bottom-up approach to health knowledge in a medically oriented scientific environment.
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Background: Biomarker research is gaining increasing attention focusing on the preclinical stages of the disease. Such interest requires special attention for communication and disclosure in clinical contexts. Many countries give dementia a high health policy priority by developing national strategies and by improving guidelines addressing disclosure of a diagnosis; however, risk communication is often neglected. Main text: This paper aims to identify the challenges of disclosure in the context of dementia prediction and to find out whether existing clinical guidelines sufficiently address the issues of disclosing a dementia diagnosis and of disclosing the risk of developing dementia in asymptomatic and MCI stage. We will examine clinical guidelines and recommendations of three countries (USA, Canada and Germany) regarding predictive testing and diagnostic disclosure in dementia and Mild Cognitive Impairment (MCI) to show their potentials and limits. This will provide a background to address ethical implications of predictive information and to identify ways how to proceed further. We will start by examining the guidelines and recommendations by focusing on what there is already and what is missing regarding the challenges of disclosing dementia prediction and MCI. Then, we will highlight the novel ethical issues generated by the shift to identify preclinical stages of the disease by biomarkers. We will argue for the need to develop guidelines for disclosing a risk status, which requires different considerations then disclosing a diagnosis of dementia. Finally, we will make some suggestions on how to address the gap and challenges raised by referring to German Stakeholder Conference, which presents us a good starting point to the applicability of involving stakeholders. Conclusions: This paper underlines the need to develop empirically based guidelines that address the ethical and social strategies for risk communication of dementia prediction by genetic as well as non-genetic biomarkers. According to our analysis, the guidelines do not address the new developments sufficiently. International efforts should aim for specific guidelines on counseling, communicating risk and disclosing results. We argue that guidelines on (risk) disclosure should be developed by involving various stakeholders and should be informed by socio-empirical studies involving laypersons' needs and wishes regarding risk communication.
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Introduction: The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown. Methods: We randomized 114 individuals with MCI to receive estimates of 3-year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non-disclosure arm) in a non-inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures. Results: Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non-inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non-disclosure arm for test-related positive impact (difference: -1.9, indicating more positive feelings) and AD concern (difference: -0.3). Discussion: Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.
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This study aimed to investigate the long-term impacts of disclosing amyloid status for a risk of Alzheimer disease (AD) to cognitively normal research participants with subjective cognitive decline (SCD), which represents an initial manifestation of AD. Forty-two participants were classified as the amyloid-positive ( n = 10) or amyloid-negative ( n = 32) groups. We assessed symptoms of anxiety, depression, and test-related distress at 6, 24, and 52 weeks after results disclosure. No difference was found over time in anxiety, depression, and test-related distress in either group. Although no significant differences were observed between groups in anxiety or depression, the amyloid-negative group had a significantly higher level of test-related distress than the amyloid-positive group at 52 weeks. Disclosing amyloid status to cognitively healthy research participants with SCD did not cause significant long-term psychological risks. However, a theoretical spectrum of subjective concern may exist about cognitive decline in amyloid-negative individuals.
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Importance Clinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer’s disease (AD) prevention, together with advances in understanding the pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals. Design The Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0. Participants 80 adults aged 65 and older: 50 who received “elevated” and 30 who received “not-elevated” amyloid PET scan results. Main outcomes Interviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors. Results Participants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid. Conclusions Clinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.
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Purpose: Mild cognitive impairment (MCI) is a widespread phenomenon, especially affecting older individuals. We will analyze in how far MCI affects different facets of quality of life (QOL). Methods: We used a sample of 903 participants (110 with MCI) from the fifth follow-up of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe), a prospective longitudinal study, to analyze the effects of MCI on different facets of the WHOQOL-OLD. We controlled for age, gender, marital status, education, living situation, daily living skills, and the ability to walk, see, and hear. Results: Univariate analyses showed that individuals with MCI exhibited lower QOL with regard to the facets autonomy; past, present, and future activities; social participation; and intimacy, but less fears related to death and dying. No significant difference was shown with regard to the facet sensory abilities. In multivariate analyses controlling for age, gender, marital status, education, living situation, daily living skills, and the ability to walk, see and hear, MCI-status was significantly associated with QOL in the facet autonomy. Conclusion: Effects of MCI go beyond cognition and significantly impact the lives of those affected. Further research and practice will benefit from utilizing specific facets of QOL rather than a total score.
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Background: Health literacy (HL) refers to the capacity to access, understand, appraise and apply information for decision-making and acting in health-related matters. In the field of Alzheimer's disease (AD), expanding technologies of early disease detection, disease course prediction and eventually personalized prevention confront individuals at-risk with increasingly complex information, which demand substantial HL skills. Here we report current findings of HL research in at-risk groups. Methods: Search strings, referring to HL, AD, amyloid and risk, were developed. A systematic review was conducted in PUBMED, Cochrane Library, PsycINFO, and Web of Science to summarize the state of evidence on HL in at-risk individuals for Alzheimer's dementia. Eligible articles needed to employ a validated tool for HL, mention the concept or one dimension (access, understand, appraise and apply information for decision-making and acting). Results: 26 quantitative and 9 qualitative studies addressing at least one dimension of HL were included. Overall, there is evidence for a wish to gain knowledge about the own brain status and risk of dementia. Psychological distress may occur and the subjective benefit-risk estimation may be modified after risk disclosure. Effects on lifestyle and planning may occur. Overall understanding and appraisal of information related to AD risk seem variable with several impacting factors. In mild cognitive impairment (MCI) basic HL skill seem to be affected by cognitive dysfunction. Conclusions: Systematic assessment of HL in at-risk population for AD is sparse. Findings indicate the paramount importance of adequate communication with persons at risk, being sensitive to individual needs and preferences. Substantial research needs were identified.
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Objectives New diagnostic criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics. Design We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey. Setting 29 secondary and tertiary memory clinics in France. Participants Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP. Primary and secondary outcome measures Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine. Results 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4). Conclusion This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.
Introduction: Recent studies suggest that Alzheimer's disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers. Methods: Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up. Results: Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms. Discussion: These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.
Background: The focus on early detection of dementia and Mild Cognitive Impairment (MCI) diagnosis has entered the clinics’ daily routine. However, there exist epistemic uncertainty and moral concerns whether early detection and prediction of dementia is clinically meaningful for the people affected, primarily due to the lack of effective treatment options. Methods: In this study, we adopted qualitative research methods. Twelve face-to-face interviews with tested persons with MCI and early dementia and five focus groups with family caregivers were conducted in Germany in order to explore and analyze their understanding and assessments of early detection and prediction of dementia in memory clinics. Results: Our study revealed that there was much uncertainty among the participants diagnosed with MCI especially when compared to the participants with an early dementia diagnosis. Their uncertainty concerned the meaning of a ‘MCI’ diagnosis as well as the validity of specific biomarker test results. Moreover, we identified different lines of moral issues for and against the tests among the participants. They include a) inter-familiar conflicts of interest in the initial phase of memory problems, b) the hope for (future) therapy and prevention, c) the desire for easier access to experts in memory clinics, d) advance planning, e) stigmatization, as well as, f) suicide as an option to avoid the future loss of self-determination. Conclusions: Current clinical and communication strategies only partly address the perspectives and needs of the affected. A standardized and ethically reflected procedure of the information provided by professionals before testing and afterwards, during disclosure, seems necessary. Further, longitudinal studies are needed to improve our knowledge about the experiences tested persons and family caregivers have with different levels of stigma.
The increasing use of biomarker tests for Alzheimer's disease (AD) in research and, to a much lesser extent, specialty care settings has led to questions concerning how individuals may react to learning of their AD biomarker status in the absence of a cure or preventative treatment. The purpose of this chapter is to systematically review the published evidence regarding amyloid imaging results disclosure and to synthesize findings across studies with a focus on the psychological, social, and behavioral outcomes of such results disclosure. Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, we searched six electronic databases, screened 265 articles, and reviewed seven publications in depth. Most studies were descriptive in nature and lack control groups. However, as a group, these articles provide important early insights into the psychological safety of disclosing amyloid imaging results to cognitively normal persons, and highlight the need for rigorously designed studies that address social and behavioral outcomes and extend to symptomatic populations.