Facilitating clinical use of the Amsterdam Instrumental Activities of Daily Living Questionnaire: Normative data and a diagnostic cutoff value.

OBJECTIVE: The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia. METHODS: Cross-sectional data from Dutch Brain Research Registry (N = 1,064; mean (M) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer's Disease 90 + (N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values (Z-scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort (N = 2,511, Mage = 64 ± 8 year, 44.4% female). RESULTS: The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97-0.98]). CONCLUSION: We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

Impact of COVID-19 pandemic on mortality rate in memory clinic patients.

INTRODUCTION: We investigated whether mortality in memory clinic patients changed due to coronavirus disease 2019 (COVID-19) pandemic. METHODS: We included patients from the Amsterdam Dementia Cohort: (1) n = 923 pandemic patients (baseline visit: 2017-2018, follow-up: until 2021), and (2) n = 830 historical control patients (baseline visit: 2015-2016, follow-up: until 2019). Groups were well-balanced. We compared mortality during pandemic with historical control patients using Cox regression. Differences in cause of death between groups were explored using Fisher's exact test. RESULTS: Pandemic patients had a higher risk of mortality than historical control patients (hazard ratio [HR] [95% confidence interval {CI}] = 1.34 [1.05-1.70]). Stratified for syndrome diagnosis, the effect remained significant in dementia patients (HR [95% CI] = 1.35 [1.03-1.78]). Excluding patients who died of COVID-19-infection, the higher mortality risk in pandemic patients attenuated (HR [95% CI] = 1.24 [0.97-1.58]). Only the difference in cause of death between pandemic patients and historical control patients for death to COVID-19-infection (p = 0.001) was observed. CONCLUSION: Memory clinic patients had increased mortality risk during COVID-19 compared to historical control patients, attributable to dementia patients. Highlights: We investigated if mortality rates in memory clinic patients changed due to COVID-19 pandemic.We included patients along the cognitive continuum, including SCD, MCI, and dementia.We used a well-balanced historical control group.Memory clinic patients had higher risk for mortality during COVID-19 lockdown.Our results indicate that excess mortality is mainly caused by death to COVID-19 infection.

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

BACKGROUND: Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical 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 sample 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 corresponding 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.

Clinical outcomes up to 9 years after [18F]flutemetamol amyloid-PET in a symptomatic memory clinic population.

BACKGROUND: Previous studies demonstrated increases in diagnostic confidence and change in patient management after amyloid-PET. However, studies investigating longitudinal outcomes over an extended period of time are limited. Therefore, we aimed to investigate clinical outcomes up to 9 years after amyloid-PET to support the clinical validity of the imaging technique. METHODS: We analyzed longitudinal data from 200 patients (Mage = 61.8, 45.5% female, MMMSE = 23.3) suspected of early-onset dementia that underwent [18F]flutemetamol-PET. Baseline amyloid status was determined through visual read (VR). Information on mortality was available with a mean follow-up of 6.7 years (range = 1.1-9.3). In a subset of 108 patients, longitudinal cognitive scores and clinical etiological diagnosis (eDx) at least 1 year after amyloid-PET acquisition were available (M = 3.06 years, range = 1.00-7.02). VR - and VR + patients were compared on mortality rates with Cox Hazard's model, prevalence of stable eDx using chi-square test, and longitudinal cognition with linear mixed models. Neuropathological data was available for 4 patients (mean delay = 3.59 ± 1.82 years, range = 1.2-6.3). RESULTS: At baseline, 184 (92.0%) patients were considered to have dementia. The majority of VR + patients had a primary etiological diagnosis of AD (122/128, 95.3%), while the VR - group consisted mostly of non-AD etiologies, most commonly frontotemporal lobar degeneration (30/72, 40.2%). Overall mortality rate was 48.5% and did not differ between VR - and VR + patients. eDx at follow-up was consistent with baseline diagnosis for 92/108 (85.2%) patients, with most changes observed in VR - cases (VR - = 14/35, 40% vs VR + = 2/73, 2.7%, χ2 = 26.03, p < 0.001), who at no time received an AD diagnosis. VR + patients declined faster than VR - patients based on MMSE (ß = - 1.17, p = 0.004), episodic memory (ß = - 0.78, p = 0.003), fluency (ß = - 1.44, p < 0.001), and attention scores (ß = 16.76, p = 0.03). Amyloid-PET assessment was in line with post-mortem confirmation in all cases; two cases were VR + and showed widespread AD pathology, while the other two cases were VR - and showed limited amyloid pathology. CONCLUSION: In a symptomatic population, we observed that amyloid-status did not impact mortality rates, but is predictive of cognitive functioning over time across several domains. Also, we show particular validity for a negative amyloid-PET assessment, as these patients did not receive an AD diagnosis at follow-up.

FindMyApps compared with usual tablet use to promote social health of community-dwelling people with mild dementia and their informal caregivers: a randomised controlled trial.

Background: FindMyApps is a tablet-based eHealth intervention designed to help people learn to use a tablet and find easy-to-use apps. This study evaluated the effectiveness of FindMyApps for supporting social health of people living with dementia, and sense of competence of their informal caregivers. Methods: A single-centre, two-arm, non-blinded randomised controlled trial was conducted (Netherlands Trial Register NL8157). From 1st January 2020 to 31st July 2022, community-dwelling people in the Netherlands with a pre-established diagnosis of mild cognitive impairment (MCI) or dementia (Brief Cognitive Rating Scale 17-32), an informal caregiver and internet connection were allocated by block randomisation to receive FindMyApps or digital care-as-usual. Primary outcomes (measured at baseline and after three months) for people with dementia/MCI were self-management (Adult Social Care Outcomes Toolkit total score) and social participation (Maastricht Social Participation Profile frequency and diversity scores), and for caregivers, sense of competence (Short Sense of Competence Questionnaire total score). Between-group differences were tested by MANCOVA or ANCOVA (alpha = 0.05). Findings: 150 dyads were randomised (FindMyApps n = 76, care-as-usual n = 74). Follow-up data were available for 128 dyads (FindMyApps n = 64, care-as-usual n = 64), who were included in the analysis in the trial arm to which they were assigned. No harms of the intervention were identified. There were no statistically significant differences in outcomes for people with dementia/MCI at group level. Diagnosis and experiencing apathy appeared to be relevant effect modifiers of secondary outcomes (neuropsychiatric symptoms, positive affect, sense of belonging, and pleasurable activities). Caregivers who received FindMyApps had higher sense of competence at three months (F [1,123] = 7.01, p = 0.0092, η2 = 0.054). Interpretation: Overall we found no evidence that the FindMyApps intervention better supported social participation or self-management of people with MCI/dementia than digital care-as-usual. FindMyApps does seem to better support informal caregivers' sense of competence. For people with a diagnosis of mild dementia and older people, better tailored interventions, implementation and outcome measures may be needed. Funding: Marie Sklodowska Curie Actions Innovative Training Network H2020 MSCA ITN, grant agreement number 813196.

Steeper memory decline after COVID-19 lockdown measures.

BACKGROUND: During COVID-19 lockdown measures, memory clinic patients reported worries for faster cognitive decline, due to loss of structure and feelings of loneliness and depression. We aimed to investigate the impact of the COVID-19 lockdown on rate of cognitive decline in a mixed memory clinic population, compared to matched historical controls. METHODS: We included patients who visited Alzheimer Center Amsterdam 6 months to 1 week before the first Dutch COVID-19 lockdown, and had a second visit 1 year later, after this lockdown period (n = 113; 66 ± 7 years old; 30% female; n = 55 dementia, n = 31 mild cognitive impairment (MCI), n = 18 subjective cognitive decline (SCD), n = 9 postponed diagnosis). Historical controls (visit in 2016/2017 and second visit 1 year later (n = 640)) were matched 1:1 to lockdown patients by optimal Mahalanobis distance matching (both groups n = 113). Groups were well matched. Differences between lockdown patients and historical controls over time in Mini-Mental State Examination, Trail Making Test part A and B, Rey-Auditory Verbal Learning Test (RAVLT) immediate and delayed recall, and category fluency scores were analyzed using linear mixed effect models with random intercepts. We examined differences in rate of cognitive decline between whole groups, and after stratification in SCD, MCI, and dementia separately. RESULTS: Lockdown patients had a faster rate of memory decline compared to controls on both RAVLT immediate [B(SE) = - 2.62 (1.07), p = 0.015] and delayed recall [B(SE) = - 1.07 (0.34), p = 0.002]. Stratification by syndrome diagnosis showed that this effect was largely attributable to non-demented participants, as we observed faster memory decline during lockdown in SCD and MCI (RAVLT immediate [SCD: B(SE) = - 6.85 (2.97), p = 0.027; MCI: B(SE) = - 6.14 (1.78), p = 0.001] and delayed recall [SCD: B(SE) = - 2.45 (1.11), p = 0.035; MCI: B(SE) = - 1.50 (0.51), p = 0.005]), but not in dementia. CONCLUSION: Memory clinic patients, specifically in pre-dementia stages, showed faster memory decline during COVID-19 lockdown, providing evidence that lockdown regulations had a deleterious effect on brain health. In individuals that may have been able to deal with accumulating, subclinical neuropathology under normal and structured circumstances, the additional stress of lockdown regulations may have acted as a "second hit," resulting in less beneficial disease trajectory.

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

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.

Testing the link between isoaspartate and Alzheimer's disease etiology.

Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (Aß) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P < 0.0001), an elevated isoAsp level in HSA (P < 0.001), more HSA aggregates (P < 0.0001), and increased levels of free Aß (P < 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with Aß and p-tau (P < 0.05). These suggest the presence in AD of a bottleneck in clearance of Aß and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there.

Changes in Brain-Health Related Modifiable Risk Factors in Older Adults After One Year of COVID-19-Restrictions.

Background: The COVID-19 pandemic has major influence on lifestyle and mental health, which might affect brain-health and increase the risk of cognitive decline, particularly in older adults. We aimed to describe changes in modifiable risk factors related to brain-health in older adults after one year of COVID-19 restrictions. Methods: An online survey was disseminated between February and March 2021 to 17,773 registrants of the Dutch Brain Research Registry, aged ≥50, without a self-reported diagnosis of mild cognitive impairment or dementia. Participants were asked to report potential changes in behaviors during the COVID-19 pandemic, compared to pre-pandemic, in eight domains related to brain health: physical activity, sleep, feeling of memory decline, perceived stress, feeling of loneliness, diet, alcohol consumption, and smoking. We used negative binomial regression analyses to relate (socio)demographics, subjective memory complaints and COVID-19 related aspects (fear of, or current/past COVID-19 infection) to the number of reported detrimental and beneficial changes as dependent variable. Results: 3,943 participants (66 ± 8 years old; 76% female; 71% highly educated) completed the survey. After one year of COVID-19-restrictions, 74% reported at least one detrimental lifestyle change unfavorable for their brain health, most frequently reported were feelings of loneliness, sleep problems, and less physical activity. 60% of participants reported at least one beneficial change, which were most often more physical activity, healthier dietary habits, and less alcohol consumption. Individuals who are younger [incidence rate ratio (IRR) = 0.99, 95% CI = 0.98-0.99], female (1.20, 1.11-1.30), living alone (1.20, 1.11-1.28) and in urban environments (1.18, 1.08-1.29), who are less satisfied with their income (1.38, 1.17-1.62), experiencing subjective memory complaints (1.40, 1.28-1.52) and those with a past or current (1.19, 1.06-1.34) or fear of a COVID-19 infection (1.33, 1.25-1.42) reported higher numbers of detrimental changes. Discussion: The COVID-19 pandemic has influenced lifestyle in both positive and negative ways. We identified (socio)demographic factors associated with more detrimental changes in modifiable risk factors related to brain health, suggesting that some individuals are more vulnerable for the impact of the COVID-19 pandemic. These findings provide an opportunity for targeted prevention and education to promote a healthy lifestyle during and after the pandemic.

Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

The Impact of Amyloid PET Disclosure on Quality of Life in Patients With Young Onset Dementia.

INTRODUCTION: The impact of amyloid positron emission tomography (PET) imaging on patient health outcomes for individuals with dementia is unknown. In the present study, we explored the association between diagnostic outcome and clinician's level of certainty with quality of life (QoL) after [18F]flutemetamol PET results were disclosed in young onset dementia patients in a memory clinic cohort. METHODS: In 154 patients suspected of dementia, QoL was measured before and after [18F]flutemetamol PET results were disclosed. Multiple regression analyses were conducted with (changed) general and disease-specific QoL measures as dependent factors [QoL-Alzheimer disease (AD) and EQ-5D Dutch tariff] and etiological diagnosis and clinician's certainty as independent factors. RESULTS: (Change in) diagnosis of AD was associated to QOL in 2 of the 4 analyses (utility-based QoL ß=0.15, P=0.010; disease-specific QoL ß=2.0, P=0.037). Diagnostic certainty was associated to QOL in 1 of the 4 analyses (generic QoL ß=0.002, P=0.028). DISCUSSION: The diverse results in this explorative analysis do not reflect a univocal association between diagnosis, certainty, and QoL. Nevertheless, this result could be interpreted as a possible potential for advanced diagnostic technologies for AD, which requires confirmation in future research.

Psychosocial Effects of COVID-19 Measures on (Pre-)Dementia Patients During Second Lockdown.

BACKGROUND: The COVID-19 pandemic poses enormous social challenges, especially during lockdown. People with cognitive decline and their caregivers are particularly at risk of lockdown consequences. OBJECTIVE: To investigate psychosocial effects in (pre-)dementia patients and caregivers during second lockdown and compare effects between first and second lockdown. METHODS: We included n = 511 (pre-)dementia patients and n = 826 caregivers from the Amsterdam Dementia Cohort and via Alzheimer Nederland. All respondents completed a self-designed survey on psychosocial effects of COVID-19. We examined relations between experienced support and psychosocial and behavioral symptoms using logistic regression. In a subset of patients and caregivers we compared responses between first and second lockdown using generalized estimating equation (GEE). RESULTS: The majority of patients (≥58%) and caregivers (≥60%) reported that family and friends, hobbies, and music helped them cope. Support from family and friends was strongly related to less negative feelings in patients (loneliness: OR = 0.3[0.1-0.6]) and caregivers (loneliness: OR = 0.2[0.1-0.3]; depression: OR = 0.4[0.2-0.5]; anxiety: OR = 0.4[0.3-0.6]; uncertainty: OR = 0.3[0.2-0.5]; fatigue: OR = 0.3[0.2-0.4]; stress: OR = 0.3[0.2-0.5]). In second lockdown, less psychosocial and behavioral symptoms were reported compared to first lockdown (patients; e.g., anxiety: 22% versus 13%, p = 0.007; apathy: 27% versus 8%, p < 0.001, caregivers; e.g., anxiety: 23% versus 16%, p = 0.033; patient's behavioral problems: 50% versus 35%, p < 0.001). Patients experienced more support (e.g., family and friends: 52% versus 93%, p < 0.001; neighbors: 28% versus 66%, p < 0.001). CONCLUSION: During second lockdown, patients and caregivers adapted to challenges posed by lockdown, as psychosocial and behavioral effects decreased, while patients experienced more social support compared to first lockdown. Support from family and friends is a major protective factor for negative outcomes in patients and caregivers.

Complementary pre-screening strategies to uncover hidden prodromal and mild Alzheimer's disease: Results from the MOPEAD project.

INTRODUCTION: The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis. METHODS: Four different strategies or RUNs were used: (a) a web-based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care-based protocol for early detection of cognitive decline (PC), and (4) a tertiary care-based pre-screening at diabetologist clinics (DC). RESULTS: A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre-screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC). CONCLUSION: These four complementary pre-screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD.

Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231.

INTRODUCTION: Studies using different assays and technologies showed highly promising diagnostic value of plasma phosphorylated (P-)tau levels for Alzheimer's disease (AD). We aimed to compare six P-tau Simoa assays, including three P-tau181 (Eli Lilly, ADx, Quanterix), one P-tau217 (Eli Lilly), and two P-tau231 (ADx, Gothenburg). METHODS: We studied the analytical (sensitivity, precision, parallelism, dilution linearity, and recovery) and clinical (40 AD dementia patients, age 66±8years, 50%F; 40 age- and sex-matched controls) performance of the assays. RESULTS: All assays showed robust analytical performance, and particularly P-tau217 Eli Lilly; P-tau231 Gothenburg and all P-tau181 assays showed robust clinical performance to differentiate AD from controls, with AUCs 0.936-0.995 (P-tau231 ADx: AUC = 0.719). Results obtained with all P-tau181 assays, P-tau217 Eli Lilly assay, and P-tau231 Gothenburg assay strongly correlated (Spearman's rho > 0.86), while correlations with P-tau231 ADx results were moderate (rho < 0.65). DISCUSSION: P-tau isoforms can be measured robustly by several novel high-sensitive Simoa assays.

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

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.

The Cognitive Online Self-Test Amsterdam (COST-A): Establishing norm scores in a community-dwelling population.

BACKGROUND: Heightened public awareness about Alzheimer's disease and dementia increases the need for at-home cognitive self-testing. We offered Cognitive Online Self-Test Amsterdam (COST-A) to independent groups of cognitively normal adults and investigated the robustness of a norm-score formula and cutoff. METHODS: Three thousand eighty-eight participants (mean age ± standard deviation = 61 ± 12 years, 70% female) completed COST-A and evaluated it. Demographically adjusted norm scores were the difference between expected COST-A scores, based on age, gender, and education, and actual scores. We applied the resulting norm-score formula to two independent cohorts. RESULTS: Participants evaluated COST-A to be of adequate difficulty and duration. Our norm-score formula was shown to be robust: ≈8% of participants in two cognitively normal cohorts had abnormal scores. A cutoff of -1.5 standard deviations proved optimal for distinguishing normal from impaired cognition. CONCLUSION: With robust norm scores, COST-A is a promising new tool for research and clinical practice, providing low cost and minimally invasive remote assessment of cognitive functioning.

A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer's Disease: Results from the MOPEAD Project.

BACKGROUND: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. OBJECTIVE: To make a cost-consequence analysis of MOPEAD. METHODS: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population. RESULTS: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. CONCLUSION: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

General practitioners' attitude toward early and pre-dementia diagnosis of AD in five European countries-A MOPEAD project survey.

INTRODUCTION: General practitioners (GPs) play a key role in early identification of dementia, yet diagnosis is often missed or delayed in primary care. As part of the multinational Models of Patient Engagement for Alzheimer's Disease project, we assess GPs' attitude toward early and pre-dementia diagnosis of AD and explore barriers to early diagnosis. METHODS: Our survey covered general attitude toward early diagnosis, diagnostic procedures, resources, and opinion on present and future treatment options across five European countries. RESULTS: In total 343 GPs completed the survey; 74% of GPs indicated that an early diagnosis is valuable. There were country-specific differences in GPs' perceptions of reimbursement and time available for the patient. If a drug were available to slow down the progression of AD, 59% of the GPs would change their implementation of early diagnosis. DISCUSSION: Our findings provide insight into GPs' attitudes by exploring differences in perception and management of early diagnosis.

Dutch Brain Research Registry for study participant recruitment: Design and first results.

INTRODUCTION: The Dutch Brain Research Registry aims to facilitate online recruitment of participants for brain disease studies. METHODS: Registrants were primarily recruited through an online social media campaign. The registration process included a short questionnaire, which was subsequently used in the prescreening process to match participants to studies. RESULTS: In the first 18 months, 17,218 registrants signed up (58±11 years old, 78% female). Out of 34,696 study invitations that were sent, 36% were accepted by registrants, of which 50% to 84% were finally enrolled, resulting in 10,661 participants in 28 studies. Compared to non-participants, study participants were more often older, male, more highly educated, retired or unemployed, non-smoking, healthier, and more often had a family member with dementia. DISCUSSION: The Dutch Brain Research Registry facilitates effective matching of participants to brain disease studies. Participant factors related to study enrollment may reflect facilitators or barriers for participation, which is useful for improving recruitment strategies.

Visual assessment of [18F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

PURPOSE: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR. METHODS: [18F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [18F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density. RESULTS: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERADSOT-based classification (i.e., any region mCERADSOT > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aß plaque was observed in all FP cases. Regional VR was also associated with regional plaque density. CONCLUSION: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.