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IntroductionThere are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100.MethodsParticipant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed.ResultsThe mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI).DiscussionAmong the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

ObjectiveTo demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.MethodParticipants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores.ResultsAcross all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial.ConclusionModern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

IntroductionThe Dutch Brain Research Registry aims to facilitate online recruitment of participants for brain disease studies.MethodsRegistrants 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.ResultsIn 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.DiscussionThe 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.

BackgroundImpairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD.MethodsIn a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized.ResultsThe rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Background: Young onset dementia (YOD) is characterized by an atypical clinical manifestation, and it is unclear to what extent impairments in everyday functioning are part of this manifestation. This study aims to describe the prevalence and differences of difficulties in instrumental activities of daily living (IADL) in YOD. Methods: In this cross‐sectional study, 394 subjects with sporadic YOD (onset<65 years,mean(M)age 58.4±standard deviation(SD)4.4 years;49.2% female) were included from the Amsterdam Dementia Cohort (ADC). Diagnoses were established in multidisciplinary consensus meetings according to disease‐specific diagnostic criteria. Everyday functioning was assessed using the proxy‐based Amsterdam IADL Questionnaire (A‐IADL‐Q). Linear regression analyses were performed to assess differences between YOD subtypes in IADL with group (YOD subtypes with AD as reference group) and IADL as outcome, adjusted for age, sex, education and disease severity (Mini Mental State Examination). A bifactor analysis was performed to identify item clusters and explore differences between groups (using linear regression). Results: The majority of sporadic YOD were diagnosed with Alzheimer's Disease (AD,n = 291(74%)), followed by Dementia with Lewy Bodies (DLB,n = 25(6%)), behavioral variant Frontotemporal Dementia (bvFTD,n = 49(12%)), Primary Progressive Aphasia (PPA,n = 20(5%)) and semantic variant Primary Progressive Aphasia (svPPA,n = 9(2%)). Most IADL difficulties were observed in DLB ((M) A‐IADL‐Q 41.8±(SD)7.78, reflecting moderate problems), and the fewest in PPA ((M)59.9±(SD)6.62, reflecting no problems)(Figure 1). When compared to AD (reference group), multiple linear regression analysis confirmed lower IADL scores for DLB (β = ‐6.37, SE = 1.63,p≤0.001), and higher for PPA (β = 10.29, SE = 1.76, p≤0.001), and svPPA (β = 6.83, SE = 2.61,p = 0.009), after adjustment for all covariates and confirmed in post‐hoc testing (Table 1). The bifactor analysis showed good reliability of the A‐IADL‐Q (Omega (ω_total) = 0.833), suggesting the presence of an underlying unimodal construct. Additional item clusters (Table 1) showed differences across groups, e.g. bvFTD showed more impairments in household activities compared to AD (β[95%CI] = ‐3.12 [‐5.64 – ‐0.61]). Further activity‐level differences can be found in Figure 2. Conclusions: Our results suggest that YOD‐subtypes differ in everyday functioning difficulties, independent of disease stage. These findings contribute to the understanding of everyday functioning difficulties in YOD, ultimately contributing to earlier recognition of the disease and personalized care. [ABSTRACT FROM AUTHOR]

Background: Verbal fluency, especially semantic fluency, may hold promise to predict clinical progression in the preclinical Alzheimer's disease (AD) stage, where patients show no objective cognitive impairment. We examined verbal fluency trajectories in amyloid‐negative and amyloid‐positive individuals with subjective cognitive decline (SCD), as well as whether baseline fluency characteristics (total scores and item‐level) predicted progression to MCI or AD dementia. Method: We retrospectively selected data of 471 Dutch individuals with SCD, with at least 1 follow‐up fluency assessment, from the Amsterdam Dementia Cohort (Follow‐up years = 4.3±2.9, Age = 61±8, Female n = 199(42%), Amyloid‐positive n = 131(28%), clinical progression n = 66(14%), Table 1). We longitudinally measured total scores for semantic (animals) and phonemic fluency (alternate versions) and semantic‐phonemic‐discrepancy scores (subtracting phonemic from semantic fluency). For a subset (n = 82) we obtained baseline item‐level characteristics: lexical frequency and word length (both continuous), errors, repetitions and duplications between semantic and phonemic fluency (all dichotomized). We compared baseline fluency measures between amyloid groups and clinical progression groups. Fluency trajectories and their associations with amyloid‐status were examined with linear mixed models. We examined associations between baseline fluency and progression to MCI/AD dementia using Cox proportional hazard models. Cox models for total and discrepancy scores were performed in the total group including a fluency*amyloid interaction, whereas models for item‐level metrics only included amyloid‐positive individuals (n = 44). All models were adjusted for age, sex and education. Results: At baseline no significant differences in any of the fluency measures between amyloid groups were observed (p's > 0.05, Table 2). Longitudinally, amyloid‐positive individuals declined more steeply on semantic fluency (β = ‐0.37,95%CI = ‐0.53—0.20) and phonemic‐semantic‐discrepancy (β = ‐0.32,95%CI = ‐0.49—0.14) compared to amyloid‐negative individuals. Groups did not differ on phonemic fluency (β = ‐0.05,95%CI = ‐0.15–0.05, Figure 1). While baseline discrepancy scores were lower in patients who later progressed (Mean = 9.0±SD = 5.4) than in non‐progressors (Mean = 10.7±SD = 5.1,W = 14317,p = 0.023), none of the baseline fluency measures predicted clinical progression after adjusting for covariates (p's>0.05). Conclusion: Longitudinal decline in semantic fluency and discrepancy scores, but not phonemic fluency, was associated with amyloid positivity in individuals with SCD. Baseline fluency did not predict clinical progression. These findings suggest that longitudinal follow‐up is essential to capture semantic fluency decline that is associated with AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer's disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden. Methods: The present study includes cross‐sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory‐clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut‐offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one‐third of the sample had available tau data). We examined four SCD‐plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD‐severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta‐analyses. Results: The overall frequency of stage 2 AD varied from 7‐16% [4‐26%] according to each SCD‐plus criterion endorsement. Only 1‐5% [0‐8%] of participants meeting the SCD‐plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self‐reported memory decline (SMD), an associated concern/worry, and a higher mean SCD‐severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same‐age peers, were not associated with AD biomarkers at a Bonferroni‐corrected threshold. Conclusions: Our results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD. [ABSTRACT FROM AUTHOR]

Background: It remains unclear to what extent global cognition translates to everyday functioning, although this is essential to interpreting the clinical meaningfulness of cognitive deficits. Here, we investigate potential linking between the Mini‐Mental State Examination (MMSE) and the proxy‐based Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q). Methods: Cross‐sectional data from 1228 amyloid‐positive participants (age = 64±7yrs; 51.1%F), with Subjective Cognitive Decline(n = 156), Mild Cognitive Impairment(n = 228) or Probable Alzheimer's Disease(n = 844) were included from the Amsterdam Dementia Cohort. Amyloid positivity was based on amyloid PET or cerebrospinal fluid, according to local cut‐off values. All participants completed MMSE, and all proxies A‐IADL‐Q. Equipercentile linking, unidimensional Item response theory (IRT) calibration and multiple regression analyses were explored as linking methods. For each MMSE quartile, we explored the proportion of reported problems on the A‐IADL‐Q total score and each A‐IADL‐Q item. We described the most commonly affected activities. Results: Assumptions for direct linking (equipercentile/IRT) were not met (r = 0.53,95%CI[0.48,0.57]). We proceeded with multiple regression analyses, with MMSE as independent variable and A‐IADL‐Q as dependent variable (adjusted for age, sex and education). Higher MMSE scores were associated with higher everyday functioning in the total sample (B =.96;95%CI[0.87,1.04]), with a one‐point increase in MMSE corresponding to nearly one additional point in A‐IADL‐Q scores. In the highest MMSE quartile (27‐30), 35% of participants experienced 'no problems', while 47%,17%, and 1% experienced 'mild,' 'moderate,' and 'severe problems' respectively (Figure 1). In the lowest quartile, 5% reported 'no problems', with 22%,44%, and 29% experiencing 'mild,' 'moderate,' and 'severe problems'. Most commonly affected activities in the highest MMSE quartile were working (74% at least mild problems), followed by using a computer (52%) and managing the household budget (47%). The latter two activities were also most commonly affected in the lowest MMSE quartile, but to a much higher degree (93%,95%) alongside filling in forms (96%). Conclusion: Although direct linking between cognition and daily functioning was not possible, our findings support more functional dependencies with increasing cognitive problems. Functional difficulties in the highest MMSE group suggest limited sensitivity of cognitive screening. Our findings suggest a nuanced link between global cognition and everyday functioning, supporting complementary use of both instruments. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) causes increasing cognitive and functional impairments, and both are therefore important outcome measures for intervention studies. Cognition and everyday functioning are often used interchangeably, yet the extent of their relationship is still unclear. We therefore aim to assess the relationship between different cognitive domains and everyday functioning across the AD spectrum. Methods: In this cross‐sectional study, we included 613 participants (Mean age ± Standard Deviation = 64 ± 8 years, n = 298(52%) female) from the memory‐clinic based Amsterdam Dementia Cohort, who were amyloid‐β positive based on cerebrospinal fluid. Cognitive functions were assessed using a standardized neuropsychological test battery assessing three domains: memory (Rey Auditory Verbal Learning Test (RAVLT) and Visual Association Test (VAT)), executive functioning (Trail Making Test‐B, Digit Span forward and backward, and letter fluency DAT) and language (animal fluency and naming condition of the VAT). Everyday functioning was assessed by the proxy‐based Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q). Structural equation modelling (SEM) analysis was performed to examine the relationship between each of the cognitive domains (i.e., composite Z‐scores) as independent variables and everyday functioning as dependent variable, adjusted for age, sex and education. The relations between latent variables (cognitive domains) were calculated while accounting for measurement error in observed variables (cognitive tests). Results: Of the 613 participants, the majority had a dementia diagnosis (n = 443, 72%), followed by mild cognitive impairment (n = 100, 16%) and subjective cognitive decline (n = 70, 11%). The SEM showed good model fit (CFI = 0.822), and confirmed that the latent cognitive domains (identified as memory, executive functioning and language) were substantially explained by their respective observed indicators with standardized estimates ranging from 0.44 to 0.91. Taking into account interdependencies and unexplained variance, the standardized estimate of memory was significantly related to the A‐IADL‐Q, demonstrating that approximately 28% of variance was explained by memory functioning. Conclusion: Memory performance was found to be uniquely related to difficulties in everyday functioning, although to a limited extent. Our findings suggest that factors beyond cognition substantially contribute to everyday functioning, highlighting that both have independent value as outcome measures. [ABSTRACT FROM AUTHOR]

Background: With the increasing number of potential interventions for Alzheimer's Disease (AD), there is a growing need to detect meaningful cognitive changes early in the disease. Frequent passive monitoring of smartphone behaviour, such as typing speed and precision, can give insight into the cognitive changes in AD. In the 'A personalized Medicine Approach for AD' (ABOARD)‐project we investigated the reliability and validity of typing behaviour to monitor cognition in people with and without AD. Method: In this prospective study we included forty participants (Healthy controls (N = 9), Subjective Cognitive Decline (N = 11), Mild Cognitive Impairment (N = 10) and dementia due to AD (N = 10)). Typing behaviour and sensor data during typing were collected for 28 days using a smartphone application (Neurokeys). Eight keystroke dynamics (KD) features were calculated (Figure 1a), standardized into z‐scores, and averaged over time to create a single score per feature. Test‐retest reliability was assessed by intra‐class correlations between the first and last 14 days. Concurrent validity was explored with correlations between the Mini‐Mental State Examination (MMSE), KD features and movement in three orthogonal directions (Figure 1b). Results: All participants completed the study with an average of 640±413 keystrokes per day (Table 1). The ICC for all features range from 0.62 to 0.88, indicating good reliability. Most KD features show moderate to strong associations with MMSE performance, including the time between characters (flight time, r = ‐0.71, p<0.001), the time between the spacebar and a next character (after‐spacebar pause, r = ‐0.65, p<0.001) and the time between the backspace and a next character (post‐correction slowing, r = ‐0.63, p<0.001, Figure 2). Movement of the phone in the X (r = 0.39, p<0.05) and Z direction (r = 0.38, p<0.05) is also correlated with the MMSE (Figure 2). Conclusion: This study provides a first indication that smartphone behaviour can be a useful and reliable tool for monitoring cognition in AD. The results suggest that individuals with worse global cognition type slower, require more time to correct an error and take more time to initiate the next word, while individuals with better cognition show more movement during typing. A larger validation study can help to confirm the potential of smartphone‐derived AD digital biomarkers. [ABSTRACT FROM AUTHOR]

With the advent of the first generation of disease‐modifying treatments for Alzheimer's disease, it is clearer now more than ever that the field needs to move toward personalized medicine. Pooling data from past trials may help identify subgroups most likely to benefit from specific treatments and thus inform future trial design. In this perspective, we report on our effort to pool data from past Alzheimer's disease trials to identify patients most likely to respond to different treatments. We delineate challenges and hurdles, from our proof‐of‐principle study, for which we requested access to trial datasets from various pharmaceutical companies and encountered obstacles in the process of arranging data‐sharing agreements through legal departments. Six phase I–III trials from three sponsors provided access to their data (total n = 3170), which included demographic information, vital signs, primary and secondary endpoints, and in a small subset, cerebrospinal fluid amyloid (n = 165, 5.2%) and tau (n = 212, 6.7%). Data could be analyzed only within specific data access platforms, limiting potential harmonization with data provided through other platforms. Limited overlap in terms of outcome measures, clinical and biological information hindered analyses. Thus, while it is a commendable advancement that (some) trials now allow researchers to study their data, we conclude that gaining access to past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals. We provide a plea to promote harmonization and open access to data, by urging trial sponsors and the academic research community alike to remove barriers to data access and improve collaboration through practicing open science and harmonizing outcome measures, to allow investigators to learn all there is to learn from past failures and successes. HIGHLIGHTS: Pooling data from past Alzheimer's disease clinical trials may help identify subgroups most likely to benefit from specific treatments and may help inform future trial design.Accessing past trial datasets is complicated, frustrating the field's communal effort to find the best treatments for the right individuals.We urge trial sponsors and the academic research community to remove data access barriers and improve collaboration through practicing open science and harmonizing outcome measures. [ABSTRACT FROM AUTHOR]

Objective: We investigated how well a visual associative learning task discriminates Alzheimer's disease (AD) dementia from other types of dementia and how it relates to AD pathology. Methods: 3,599 patients (63.9 ± 8.9 years old, 41% female) from the Amsterdam Dementia Cohort completed two sets of the Visual Association Test (VAT) in a single test session and underwent magnetic resonance imaging. We performed receiver operating curve analysis to investigate the VAT's discriminatory ability between AD dementia and other diagnoses and compared it to that of other episodic memory tests. We tested associations between VAT performance and medial temporal lobe atrophy (MTA), and amyloid status (n = 2,769, 77%). Results: Patients with AD dementia performed worse on the VAT than all other patients. The VAT discriminated well between AD and other types of dementia (area under the curve range 0.70–0.86), better than other episodic memory tests. Six-hundred forty patients (17.8%) learned all associations on VAT-A, but not on VAT-B, and they were more likely to have higher MTA scores (odds ratios range 1.63 (MTA 0.5) through 5.13 for MTA ≥ 3, all p <.001) and to be amyloid positive (odds ratio = 3.38, 95%CI = [2.71, 4.22], p <.001) than patients who learned all associations on both sets. Conclusions: Performance on the VAT, especially on a second set administered immediately after the first, discriminates AD from other types of dementia and is associated with MTA and amyloid positivity. The VAT might be a useful, simple tool to assess early episodic memory deficits in the presence of AD pathology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real‐world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real‐world settings. [ABSTRACT FROM AUTHOR]