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Deciding on genetic testing for familial dementia: Perspectives of patients and families

Jetske van der Schaar, Sven J van der Lee, Eva C A Asscher, Yolande A L Pijnenburg, Christa M de Geus, Annelien L Bredenoord, Wiesje M van der Flier, Mariette A van den Hoven, Ellen M A Smets, Leonie N C Visser

 

Abstract

Introduction

We explored patients’ and families’ interest in, predictors of, and considerations regarding genetic testing for monogenic causes of dementia in a diagnostic setting.

Methods

This mixed‐methods study evaluated 519 consecutive Alzheimer Center Amsterdam patients for monogenic testing eligibility. Among those qualifying, differences between testers and non‐testers were analyzed. Thirty‐three patients completed questionnaires. Additionally, we conducted 21 semi‐structured interviews with 15 patients and 18 relatives. Verbatim transcripts were analyzed inductively.

Results

Of 138 (27%) eligible patients (46% female, age 61 ± 8 years, Mini‐Mental State Examination [MMSE] 22 ± 6), 75 (54%) underwent genetic testing. Testers had better cognition, higher quality of life, and more often undetermined diagnoses than non‐testers (all p < 0.05). Decisions were guided by intuitive, value‐driven judgments: testers sought to provide heredity information to relatives, enhance actionability, and reduce uncertainty, while non‐testers worried about psychosocial impact on family, or unfavorable timing.

Discussion

The substantial interest in genetic testing for monogenic causes of dementia underscores the need for further research into the implications of disclosing test results to memory clinic patients.

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Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic

Sven J. Van Der Lee, Marc Hulsman, Rosalina Van Spaendonk, Jetske Van Der Schaar, Janna Dijkstra, Niccoló Tesi, Fred van Ruissen, Mariet Elting, Marcel Reinders, Itziar De Rojas, Corien C. Verschuuren-Bemelmans, Wiesje M. Van Der Flier, Mieke M. van Haelst, Christa de Geus, Yolande Pijnenburg, and Henne Holstege

 

Abstract

Background and Objectives

Identifying genetic causes of dementia in patients visiting memory clinics is important for patient care and family planning. Traditional clinical selection criteria for genetic testing may miss carriers of pathogenic variants in dementia-related genes. This study aimed identify how many carriers we are missing and to optimize criteria for selecting patients for genetic counseling in memory clinics.

Methods

In this clinical cohort study, we retrospectively genetically tested patients during 2.5 years (2010–2012) visiting the Alzheimer Center Amsterdam, a specialized memory clinic. Genetic tests consisted of a 54-gene dementia panel, focusing on Class IV/V variants per American College of Medical Genetics and Genomics guidelines, including APP duplications and the C9ORF72 repeat expansion. We determined the prevalence of pathogenic variants and propose new eligibility criteria for genetic testing in memory clinics. The eligibility criteria were prospectively applied for 1 year (2021–2022), and results were compared with the retrospective cohort.

Results

Genetic tests were retrospectively performed in in 1,022 of 1,138 patients (90%) who consecutively visited the memory clinic. Among these, 1,022 patients analyzed (mean age 62.1 ± 8.9 years; 40.4% were female), 34 pathogenic variant carriers were identified (3.3%), with 24 being symptomatic. Previous clinical criteria would have identified only 15 carriers (44% of all carriers, 65% of symptomatic carriers). The proposed criteria increased identification to 22 carriers (62.5% of all carriers, 91% of symptomatic carriers). In the prospective cohort, 148 (28.7%) of 515 patients were eligible for testing under the new criteria. Of the 90 eligible patients who consented to testing, 13 pathogenic carriers were identified, representing a 73% increase compared with the previous criteria.

Discussion

We found that patients who visit a memory clinic and carry a pathogenic genetic variant are often not eligible for genetic testing. The proposed new criteria improve the identification of patients with a genetic cause for their cognitive complaints. In systems without practical or financial barriers to genetic testing, the new criteria can enhance personalized care. In other countries where the health care systems differs and in other genetic ancestry groups, the performance of the criteria may be different.

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The need for personalization when sharing results of amyloid imaging for Alzheimer’s disease: Insights from a randomized experimental study

Agnetha D. Fruijtier, Wiesje M. van der Flier, Ingrid van Maurik, Jetske van der Schaar, Yolande A.L. Pijnenburg, Ellen M.A. Smets, Leonie N.C. Visser

 

Abstract

Introduction

To study information needs after receiving abnormal amyloid-PET results, and how individual characteristics moderate effects of different communication strategies on information recall.

Methods

In an online video-vignette experiment, seven vignettes each depicted a consultation of a physician sharing abnormal amyloid-PET results with a patient with Mild Cognitive Impairment(MCI), using different communication strategies. Healthy individuals (N = 1017; age 64 ± 8, 808(79 %) female), instructed to imagine themselves as the video-patient, viewed a randomly-assigned vignette and completed questionnaires to assess information needs and test moderation effects of gender, age, care-partner experience, health literacy, and coping.

Results

Sixty-three percent of participants (645/1017) would have liked to receive more information, e.g., on prognosis, additional information sources, lifestyle advice, and/or treatment. Emotional support benefited information recall in women, but not men. Emotional support and visually presenting the PET-scan were less beneficial for individuals with a stronger avoidant coping style, compared to most other strategies.

Conclusions

Most people wanted more information on varying topics, and gender and coping style influenced how communication strategies impacted information recall.

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Amyloid PET disclosure in subjective cognitive decline: Patient experiences over time

Heleen M. A. Hendriksen, Tanja J. de Rijke, Agnetha Fruijtier, Elsmarieke van de Giessen, Argonde C. van Harten, Mardou S. S. A. van Leeuwenstijn-Koopman, Jetske van der Schaar, Calvin Trieu, Denise Visser, Ellen M. A. Smets, Leonie N. C. Visser and Wiesje M. van der Flier

 

Abstract

Introduction

We disclosed amyloid positron emission tomography (PET) results in individuals with subjective cognitive decline (SCD) and studied patient experiences and outcomes over a 6-month period.

Methods

Fifty-seven participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (66 ± 8 years, 21 [37%] F, Mini-Mental State Examination 29 ± 1, 15 [26%] amyloid positive [A+]) completed questionnaires 1 week prior (T0), 1 day after (T1), and 6 months after amyloid PET disclosure (T2). Questionnaires addressed patient-reported experiences and outcomes.

Results

Independent of amyloid status, participants were satisfied with the consultation (scale 1–10; 7.9 ± 1.7) and information provided (scale 1–4; T1: 3.3 ± 0.9, T2: 3.2 ± 0.8). After 6 months, A+ participants reported more information needs (45% vs. 12%, p = 0.02). Independent of amyloid status, decision regret (scale 1–5; A+: 1.5 ± 0.9, A−: 1.4 ± 0.6, p = 0.53) and negative emotions (negative affect, uncertainty, anxiety) were low (all p > 0.15 and Pinteraction > 0.60).

Conclusions

Participants with SCD valued amyloid PET disclosure positively, regardless of amyloid status. The need for information after 6 months, which was stronger in A+ individuals, underscores the importance of follow-up.

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Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study

Lisa Waterink, Larissa A. Masselink, Sven J. van der Lee, Leonie N. C. Visser, Solange Cleutjens, Jetske van der Schaar, Argonde C. van Harten, Philip Scheltens, Sietske A. M. Sikkes, Wiesje M. van der Flier and Marissa D. Zwan

 

Abstract

Background

Apolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clini- cal trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one’s genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sam- ple of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.

Methods

An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran’s Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.

Results

Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower- educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements, e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk.

Conclusions

Our findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios correspond- ing to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well- received method to accelerate inclusion for trials.

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Impact of sharing Alzheimer’s disease biomarkers with individuals without dementia: A systematic review and meta-analysis of empirical data

Jetske van der Schaar, Leonie N. C. Visser, Johannes C. F. Ket, Colin Groot, Yolande A. L. Pijnenburg, Philip Scheltens, Annelien L. Bredenoord, Mariëtte A. van den Hoven, Wiesje M. van der Flier

 

Abstract

Introduction

We conducted a systematic literature review and meta-analysis of empirical evidence on expected and experienced implications of sharing Alzheimer’s disease (AD) biomarker results with individuals without dementia.

Methods

PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results from included studies were synthesized, and quantitative data on psychosocial impact were meta-analyzed using a random-effects model.

Results

We included 35 publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta-analysis of five studies including 2012 participants (elevated amyloid = 1324 [66%], asymptomatic = 1855 [92%]) showed short-term psychological impact was not significant (random-effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional stakeholders valued biomarker testing, although attitudes and practices varied considerably.

Conclusions

Interest in AD biomarker testing was high and sharing their results did not cause psychological harm.

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Identifying best practices for disclosure of amyloid imaging results: A randomized controlled trial

Agnetha D Fruijtier, Jetske van der Schaar, Ingrid S van Maurik, Marissa D Zwan, Philip Scheltens, Femke Bouwman, Yolande A L Pijnenburg, Bart N M van Berckel, Jarith Ebenau, Wiesje M van der Flier, Ellen M A Smets, Leonie N C Visser

 

Abstract

Introduction: Empirical studies on effective communication for amyloid disclosure in mild cognitive impairment (MCI) are lacking. We aimed to study the impact of six communication strategies.

Method: We performed a randomized controlled trial with seven randomly assigned, video-vignette conditions: six emphasizing a communication strategy and one basic condition. All showed a scripted consultation of a neurologist disclosing positive amyloid positron emission tomography (PET) scan results to an MCI patient. Healthy individuals (N = 1017; mean age ± SD 64 ± 8, 808 (79%) female) were instructed to imagine themselves in the video, answered questionnaires assessing information recall, emotional state, and behavioral intentions, and evaluate the physician/information.

Results: “Risk best practice” resulted in highest free recall compared to other strategies (P < .05), except “emotional support”. Recall in “emotional support” was better compared to “basic-‘ and elaborate information”(P < .05). “Risk best practice” resulted in the highest uncertainty (P < .001). “Teach-back” and “emotional support” contributed to the highest evaluations (P -values < .01).

Conclusion: Risk communication best practices, attending to emotions, and teach-back techniques enhance information recall of amyloid-PET results, and could contribute to positive care evaluations.

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Considerations regarding a diagnosis of Alzheimer’s disease before dementia: a systematic review

Jetske van der Schaar, Leonie N. C. Visser, Femke H. Bouwman, Johannes C. F. Ket, Philip Scheltens, Annelien L. Bredenoord & Wiesje M. van der Flier

 

Abstract

Background

The NIA-AA research framework proposes a purely biological definition of Alzheimer’s disease (AD). This implies that AD can be diagnosed based on biomarker abnormalities, irrespective of clinical manifestation. While this brings opportunities, it also raises challenges. We aimed to provide an overview of considerations regarding the disclosure of AD pathology before the onset of dementia.

Methods

A systematic literature review was conducted and reported according to PRISMA guidelines. We searched PubMed, Embase, APA PsycINFO, and Web of Science Core Collection (on 10 December 2020) for references on conveying AD biomarker results to individuals without dementia. Our query combined variations on the terms Alzheimer’s disease, disclosure, or diagnosis, preclinical or prodromal, and biomarkers. Two reviewers independently screened the resulting 6860 titles and abstracts for eligibility and examined 162 full-text records for relevance. We included theoretical articles in English, on communicating amyloid and/or tau results to individuals with mild cognitive impairment, subjective cognitive decline, or normal cognition. MAXQDA-software was used for inductive data analysis.

Results

We included 27 publications. From these, we extracted 26 unique considerations, which we grouped according to their primary relevance to a clinical, personal, or societal context. Clinical considerations included (lack of) validity, utility, and disclosure protocols. Personal considerations covered psychological and behavioral implications, as well as the right to (not) know. Finally, societal considerations comprised the risk of misconception, stigmatization, and discrimination. Overall, views were heterogeneous and often contradictory, with emphasis on harmful effects.

Conclusions

We found 26 diverse and opposing considerations, related to a clinical, personal, or societal context, which are relevant to diagnosing AD before dementia. The theoretical literature tended to focus on adverse impact and rely on common morality, while the motivation for and implications of biomarker testing are deeply personal. Our findings provide a starting point for clinicians to discuss biomarker-based diagnosis with their patients, which will become even more relevant in light of the conditional approval of a first disease-modifying drug for AD.

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Dementia risk communication. A user manual for Brain Health Services—part 3 of 6

Leonie N. C. Visser, Carolina Minguillon, Gonzalo Sánchez-Benavides, Marc Abramowicz, Daniele Altomare , Karine Fauria, Giovanni B. Frisoni, Jean Georges, Federica Ribaldi, Philip Scheltens, Jetske van der Schaar, Marissa Zwan, Wiesje M. van der Flier, and José Luis Molinuevo

 

Abstract

Growing evidence suggests dementia incidence can be reduced through prevention programs targeting risk factors. To accelerate the implementation of such prevention programs, a new generation of brain health services (BHS) is envisioned, involving risk profiling, risk communication, risk reduction, and cognitive enhancement. The
purpose of risk communication is to enable individuals at risk to make informed decisions and take action to protect themselves and is thus a crucial step in tailored prevention strategies of the dementia incidence. However, communicating about dementia risk is complex and challenging.

In this paper, we provide an overview of (i) perspectives on communicating dementia risk from an ethical, clinical, and societal viewpoint; (ii) insights gained from memory clinical practice; (iii) available evidence on the impact of disclosing APOE and Alzheimer’s disease biomarker test results gathered from clinical trials and observational
studies; (iv) the value of established registries in light of BHS; and (v) practical recommendations regarding effective strategies for communicating about dementia risk.

In addition, we identify challenges, i.e., the current lack of evidence on what to tell on an individual level—the actual risk—and on how to optimally communicate about dementia risk, especially concerning worried yet cognitively unimpaired individuals. Ideally, dementia risk communication strategies should maximize the desired
impact of risk information on individuals’ understanding of their health/disease status and risk perception and minimize potential harms. More research is thus warranted on the impact of dementia risk communication, to (1) evaluate the merits of different approaches to risk communication on outcomes in the cognitive, affective and
behavioral domains, (2) develop an evidence-based, harmonized dementia risk communication protocol, and (3) develop e-tools to support and promote adherence to this protocol in BHSs.

Based on the research reviewed, we recommend that dementia risk communication should be precise; include the use of absolute risks, visual displays, and time frames; based on a process of shared decision-making; and address the inherent uncertainty that comes with any probability.

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