Jetske van der Schaar

Background: Biomarker assessments increasingly inform the diagnostic evaluation and treatment decisions in Alzheimer disease (AD). However, evidence on the impact of amyloid positron emission tomography (PET) disclosure is primarily derived from studies of cognitively unimpaired trial participants with follow-up limited to 18 months. In contrast, long-term implications for individuals with cognitive concerns who seek medical evaluation in memory clinics remain unknown. We aimed to examine the psychosocial and behavioral impact three years after amyloid PET disclosure in individuals presenting with subjective cognitive decline (SCD) at a memory clinic. Methods: In-depth semi-structured interviews were conducted with 17 participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (67 ± 7 years; 5 female; 10 amyloid positive) 35 ± 4 months post-disclosure. All had SCD at imaging; one had progressed to mild cognitive impairment (MCI) at interview. Verbatim transcripts were analyzed inductively. Results: Participants’ motivations for testing and long-term adaptation to the results were strongly shaped by cognitive concerns and personal experiences of dementia in relatives. All demonstrated accurate comprehension of their amyloid status. Those with negative scans described immediate relief and reattributed memory lapses to normal aging, while recognizing that the reassurance was provisional. Although positive scans provoked initial shock and fear of deterioration, participants valued information over uncertainty, and over time, fear attenuated as they perceived no rapid decline. Both groups regarded results as meaningful and personally actionable, informing health behavior, life priorities, and preparations for future decline. Fourteen of 17 participants spontaneously mentioned considering options for self-determined end-of-life. Regardless of amyloid status, most participants shared their result with close relatives and friends, some also informed colleagues or acquaintances, while others limited communication to avoid stigma, protect loved ones, or reduce the burden of repeated explanations. Participants valued testing, expressed no regret, and would choose disclosure again. Conclusions: Three years after disclosure, participants generally had adjusted to living with their imaging result, finding personal meaning and practical engagement without reporting ongoing psychological harm. Some reported residual concerns and uncertainty, irrespective of amyloid status. These findings offer timely guidance for clinicians and patients as biomarker disclosure is more widely incorporated into routine practice.

Background: While memory clinic patients express interest in diagnostic genetic testing for monogenic causes of dementia, its personal consequences remain unclear. We explored the psychosocial and behavioral impact on patients and relatives. Methods: In this mixed-methods study, we examined 31 patients meeting eligibility criteria for genetic testing as part of their diagnostic work-up at Alzheimer Center Amsterdam. Patients were 45% female, and aged 61 ± 8 (MMSE = 23 ± 5, 25 dementia [15 AD, 4 PPA, 6 other], 1 MCI, 1 SCD, 4 other/undetermined). Twenty-five tested negative, and six positive. Per case, either the patient, one or more relatives, or both were included (3/31 patient only; 5/31 relative(s) only; 23/31 both), yielding 26 patients and 29 relatives (55% female, and aged 54 ± 12). Participants completed questionnaires assessing psychosocial and behavioral factors at first visit, one week post-counseling, and one week and three months post-disclosure. We used linear mixed models to calculate effects of group, time, and interaction, with patients and relatives analyzed separately. In addition, 8 patients and 10 relatives participated in 13 semi-structured interviews, analyzed inductively. Results: Average anxiety, depression and distress levels remained below clinical threshold in patients and relatives. Anxiety was lower in patients one week and three months post-disclosure, and lower in relatives one week post-disclosure. At baseline, positive patients reported lower social support, and over time they discussed genetic testing less often with others. Positive patients more often reported having registered for research participation. Patients’ decision regret was low and independent of group. Interviews revealed that participants receiving negative results felt relieved their offspring were not at genetic risk, but some remained uncertain about the cause of their disease. Those receiving positive results experienced emotional distress about potential implications for their children, yet appreciated having clarity. Participants related to positive cases described challenges in receiving emotional support. Conclusions: While diagnostic genetic testing was well tolerated and valued, it also revealed complex emotional, relational, and practical consequences for patients and families, indicating a need for psychosocial support. As this was an exploratory study, findings should be interpreted cautiously and validated in future research.

Background: Memory clinic patients are interested in genetic testing for monogenic causes of dementia, but it remains unknown how they experience receiving the results. We explored the psychosocial and behavioral impact of DNA diagnostics on patients and their families. Methods: In this mixed‐methods study, 37 patients visiting Alzheimer Center Amsterdam, meeting eligibility criteria, were offered genetic testing for monogenic causes as part of their diagnostic work‐up. Patients were 41% female and aged 61±7 years (MMSE=22±5, 1 Subjective Cognitive Decline, 1 MCI, 30 dementia [20 AD, 4 PPA, 6 other], 5 other/undetermined). Six declined testing, 25 tested negative and six positive. Per potential proband, we included patients ( n = 4), one or two relatives ( n = 4), or both ( n = 29). Relatives ( n = 34) were 59% female, and aged 54±13. Participants completed questionnaires assessing psychosocial and behavioral factors (including anxiety, depression and distress) at first visit, one week after counseling, one week and three months after disclosure. We used linear mixed models to calculate effects of group (un‐tested, negative, or positive), time, and interactions on outcome variables, with patients and relatives analyzed separately. In addition, 9 patients and 11 relatives participated in 14 semi‐structured interviews. Verbatim transcripts were analyzed inductively. Results: Average anxiety, depression and distress levels remained below clinical threshold and did not change between groups or over time, in patients nor relatives (see figures). Three months after disclosure, patients tested positive showed an increase in perceived risk of carrying a monogenic cause (β=48.55, 95%CI[9.17,87.93], p p 0.05). Interviews revealed patients tested negative were relieved, reassured their offspring were not at genetic risk, but sometimes unsatisfied for not knowing the cause of their disease. Those tested positive appreciated having clarity, yet experienced emotional distress about potential implications for their children. Conclusions: Genetic testing for monogenic causes of dementia did not cause short‐term psychosocial harm. Patients understood the gist of the results, deemed them actionable and reported no regret. Further research in larger populations should confirm and expand upon these findings.

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.Highlights: Half of memory clinic patients’ who met eligibility criteria proceeded with genetic testing. Those tested were more likely to have an undetermined diagnosis, better cognition, and higher quality of life. Decisions were motivated less by deliberation of factual information, and more by quick, intuitive judgments. Motivations pro included providing information, enhancing actionability, and resolving uncertainty. Motivations con comprised concerns about the emotional burden and disruptive impact on their family.

Background: Data‐driven criteria for DNA testing were implemented in routine care of Alzheimer Center Amsterdam. We aimed to explore patients’ perspectives and considerations regarding their decision to (not) be tested for a monogenic cause of their disease.Methods: In this mixed method study, 150 of 519 new patients visiting Alzheimer Center Amsterdam who fulfilled the criteria were offered DNA‐diagnostics: 86(57%) accepted, 64(43%) did not. In 65/86(76%) cases results were negative, in 14/86(16%) a monogenic cause and in 7/86 (8%) variants of uncertain significance were found (Figure 1). Sex, age, education, family history of dementia, MMSE and diagnosis were retrieved. Before discussing DNA testing, patients completed a questionnaire assessing perceived risk of a genetic cause, susceptibility for, severity of, and experience with dementia, social support, coping strategies, anxiety, depression, and quality of life. Differences between those who did and did not consent to DNA testing were calculated using Pearson’s χ², Mann‐Whitney U or Independent Samples t‐tests; p‐values were FDR‐adjusted. A subset of 22 patients and/or relatives participated in semi‐structured interviews on motivations and considerations regarding their decision. Verbatim transcripts were analyzed inductively using MAXQDA‐software.Results: Participants (n = 150) were 46% female and aged 61±8 (MMSE = 22±6, 5 Subjective Cognitive Decline, 9 MCI, 104 dementia [69 AD, 13 FTD, 22 other], 32 other/undetermined). Adjusted for multiple testing, no demographic, medical or psychosocial factors were associated with the decision on DNA testing (all p>0.05). Twenty‐one interviewees who agreed to DNA testing were generally motivated by obtaining information on heredity for their relatives, contributing to scientific research into a treatment, and gaining insight in the cause of their disease. One patient had blood stored, allowing their children to test it when opportune. The majority decided quickly, mostly on intuitions (e.g., responsibility towards relatives) rather than facts (e.g., information on risk and consequences). They expected to feel reassured or relieved by negative test results, and sad or worried if a genetic cause was found.Conclusions: Over half of memory clinic patients eligible for DNA‐testing wanted to be tested. This decision was unrelated to demographic, medical or psychosocial characteristics, and mostly based on intuition and considerations regarding family.

Importance Identifying genetic causes for dementia in patients who visit a memory clinic is important for patients and family members. However, current clinical selection criteria for genetic analysis may miss carriers of pathogenic genetic variants (PGVs) in dementia-related genes. Objective Optimizing the patient-selection criteria for offering genetic counselling in patients visiting memory clinics. Design Clinical cohort study at the Alzheimer Center Amsterdam, analysing patients from January 2010 to June 2012, and who participated in the Amsterdam Dementia Cohort. A 54-gene dementia panel was used to identify PGVs, class IV/V variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Subsequently, we formulated a novel decision tree to determine eligibility for genetic testing, allowing optimal identification of symptomatic PGV carriers. The decision tree was prospectively applied in the same memory clinic for one year (2021-2022). Setting The Alzheimer Center Amsterdam, a specialized memory clinic in the Netherlands. Participants A total of 1,138 patients visited the memory clinic (2010-2012), of whom 1,022 were genetically analysed [90%]. Of the analysed patients 413 were female [40.4%], mean [SD] age at presentation 62.1 [8.9] years. The decision tree was applied to 517 patients that visited the memory clinic between 2021-2022; 215[41.6%] female, mean [SD] age at presentation 64.1[8.5] years. Exposure none Main Outcome(s) Presence of a PGVs and eligibility of carriers for genetic testing based on previous and new clinical selection criteria. Results We identified 34 PGV carriers, corresponding to 3.3% of all patients. Of these, 24 carriers had symptoms of dementia [n=24]. Based on previous clinical criteria, only 15 of all PGV carriers were eligible. Which was 44% of all PGV carriers [15/34] and 65% of symptomatic PGV carriers [15/24]. With the new decision tree, 22 of all PGVs were eligible 62.5% [22/34] and 91% [22/24] of all symptomatic PGV carriers were eligible. In the prospective application, 517 patients were evaluated of which 148[31%] patients were eligible for a genetic test, 103 [20%] were finally tested and 13 patients carried a PGV [2.5% of total]. There were 73% more patients with a PGV identified than anticipated. Conclusions and Relevance Our decision tree improved the identification of patients with genetic dementias. Question Do current clinical criteria for selecting dementia patients identify those with pathogenic genetic variants (PGVs) in dementia-related genes? Findings In a cohort study at the Alzheimer Center Amsterdam, 34 PGV carriers were identified among 1,022 patients. Previous criteria identified only 44% (15/34) of all carriers and 65% (15/24) of symptomatic carriers. A new decision tree increased this to 62.5% (22/34) and 91% (22/24), respectively. Real-life implementation improved carrier identification by 73%. Meaning Our decision tree enhances genetic dementia patient identification, offering an improved approach to identify families with familial dementia.

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.Discussion: Interest in AD biomarker testing was high and sharing their results did not cause psychological harm.Highlights: Most personal stakeholders expressed interest in Alzheimer's disease biomarker assessment. Personal motivations included gaining insight, improving lifestyle, or preparing for the future. There was no short‐term psychological impact of sharing biomarker status, implying it can be safe. Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risk. Harmonized guidelines on biomarker testing and sharing results are required.

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.

Introduction The NIA-AA research framework proposes a purely biological definition of Alzheimer’s Disease (AD). This implies AD can be diagnosed based on biomarker abnormalities. While this brings opportunities, it also raises challenges. Methods We conducted a systematic review by searching PubMed for publications on conveying AD biomarker results to individuals without dementia. Content was analyzed inductively. Results We included 25 publications. From these we extracted 26 considerations, which we grouped according to their primary relevance to a clinical, personal, or societal context. Clinical considerations include (lack of) validity, utility, and disclosure protocols. Personal considerations cover psychological and behavioral implications, as well as the right to (not) know. Societal considerations comprise the risk of misconception, stigmatization, and discrimination. Overall, views were heterogeneous and often contradictory. Discussion Perceptions on a diagnosis of AD before dementia vary widely. Empirical research is required, taking perspectives of medical professionals and the general public into account.