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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]

Objective: Neuropsychological assessment through VideoTeleConferencing (VTC) can help improve access to diagnostic and follow-up care in memory clinics. This study investigated the stability of performance on VTC assessment in relation to in-person assessment using a test-retest design and explored user experiences of VTC assessment. Materials and Methods: Thirty-one patients (62 ± 6.7 years, 45% female, 58% Subjective Cognitive Decline, 42% Mild Cognitive Impairment/dementia diagnosis) were included from the Amsterdam Dementia Cohort between August 2020 and February 2021. Patients underwent a face-to-face neuropsychological assessment followed by a VTC assessment using the same test protocol within 4 months. Reliability coefficients were calculated using intraclass correlation coefficients (ICC). For each test, the proportion of clinically relevant differences in performances between assessment modalities was calculated. User experiences of patients and neuropsychologists were assessed with questionnaires (User Satisfaction and Ease of use [USE] questionnaire and System Usability Scale [SUS]). Neuropsychologists also participated in a focus group. Results: ICC values were moderate to excellent (0.63-0.93) for all test measures in the total sample. On all tests, most patients did not show clinically relevant performance differences between modalities. Patients and neuropsychologists reported overall positive VTC system usability, although neuropsychologists indicated in the focus group that patients without cognitive impairment required less training for the system and were more independent. Conclusion: VTC assessment showed adequate to excellent test-retest reliability for a broad range of neuropsychological tests commonly used in practice. Assessment through VTC may be a user friendly method in the memory clinic, especially to monitor individuals at risk for future cognitive decline. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to compare and link the total scores of the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), two common global cognitive screeners. Methods: 2,325 memory clinic patients (63.2 ± 8.6 years; 43% female) with a variety of diagnoses, including subjective cognitive decline, mild cognitive impairment, and dementia due to various etiologies completed the MMSE and MoCA concurrently. We described both screeners, including at the item level. Then, using linear regressions, we investigated how age, sex, education, and diagnosis affected total scores on both instruments. Next, in linear mixed models, we treated the two screeners as repeated measures and analyzed the influence of these characteristics on the relationship between the instruments' total scores. Finally, we linked total scores using equipercentile equating, accounting for relevant patient characteristics. Results: MMSE scores (mean ± standard deviation: 25.0 ± 4.6) were higher than MoCA scores (21.2 ± 5.4), and MMSE items generally showed less variation than MoCA items. Both instruments' scores were individually influenced by age, sex, education, and diagnosis. The relationship between the screeners was moderated by age (estimate = −0.01, 95% confidence interval = [−0.03, −0.00]), education (0.14 [0.10, 0.18]), and diagnosis. These were accounted for when producing crosswalk tables based on equipercentile equating. Conclusions: Accounting for the influence of patient characteristics, we created crosswalk tables to convert MMSE scores to MoCA scores, and vice versa. These tables may facilitate collaboration between clinicians and researchers and could allow larger, pooled analyses of global cognitive functioning in older adults. [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]

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]

Background: The Amsterdam Instrumental ADL Questionnaire (A‐IADL‐Q) has shown promising performance in detecting subtle impairment in IADL independency. Importantly, it has not been validated in older people in a primary care setting, i.e., where the initial work‐up and triaging of cognitive impairment occurs. The main aim was to examine the accuracy of the A‐IADL‐Q for estimating the cognitive stage in a primary care sample, both in the whole population and within the Alzheimer's disease (AD) continuum. Secondary aims were to examine associations with the clinical dementia rating (CDR) scale and global cognition (MMSE), including the effects of non‐cognitive co‐morbidities and medications. Method: This cross‐sectional study includes informants of 362 participants from the BioFINDER‐Primary care study. They completed the A‐IADL‐Q (higher scores = "better") either on an iPad or at home on a computer. Cognitive stage was assessed by a dementia expert (blinded to A‐IADL‐Q scores). Amyloid status was determined using FDA‐approved CSF or PET measures. The main outcome was cognitive stage according to the NIA‐AA scale. Secondary outcomes were CDR‐sum of the boxes (CDR‐SOB) and MMSE. Receiver Operating Curves (ROC) analyses were used to calculate the area under the curves (AUCs). Result: The mean age of participants (44.9% female) was 76.1 (SD 7.2) years. Out of which, 83 (23%) had subjective cognitive decline (SCD), 169 (47%) mild cognitive impairment (MCI), and 110 (30%) dementia. The AUC (95% CI) for differentiating between SCD versus MCI/dementia was 0.89 (0.85‐0.92), and it was 0.89 (0.85‐0.93) for SCD/MCI versus dementia. In amyloid positive participants (n = 303), AUCs were similar. Better A‐IADL‐Q scores were associated with worse results on CDR‐SOB (r = ‐0.73, p<0.001) and better global cognition (MMSE, r = 0.361, p<0.001). The effects of different co‐morbidities on the A‐IADL score, adjusted for cognitive stage, will be presented at AAIC. Conclusion: Our findings suggest that the A‐IADL‐Q accurately estimates the cognitive stage among cognitively impaired older people (with high prevalence of comorbidities) in a primary care setting. This can aid primary care physicians in the diagnosis of cognitive impairment, clinical management/support, and as part of the work‐up for identifying eligible participants for anti‐amyloid treatment. [ABSTRACT FROM AUTHOR]

Background: Automated analysis of natural speech is emerging as a promising digital biomarker of Alzheimer's disease (AD). As speech is a complex process, relying on multiple interacting cognitive functions, fine‐grained analysis of speech may have the potential to capture subtle cognitive deficits in the very early stages of AD. Here, we examined the association between amyloid‐beta (Aβ) pathology and acoustic speech characteristics in a group of cognitively normal Dutch adults. Method: We included 50 cognitively normal (n = 23 Aβ‐positive, 46%) older adults from three clinical cohorts at the Alzheimer Center Amsterdam (Table 1). Aβ‐status was based on local cut‐offs for Aβ1‐42‐concentrations in cerebrospinal‐fluid or visual inspection of amyloid positron emission tomography (PET)‐imaging. In a five day remote burst assessment, seventeen tablet‐based tasks (picture description, journal‐prompt storytelling, verbal‐fluency) were administered, with a daily administration time of approximately 10 minutes. Various acoustic features, including silent pauses, pause‐to‐word‐ratio, and perceived loudness, were extracted from the voice recordings. Mean burst scores were calculated over the five‐day period. The association between Aβ‐pathology and acoustic features was investigated using linear regression models separately for each subtask. Results: Pause‐to‐word ratio was higher in Aβ‐positive individuals in the repetitive picture description subtask (β = ‐0.05, p = 0.04) and the journaling subtask (β = ‐0.07, p = 0.03) compared to the Aβ‐negative individuals. Although statistical significance between groups was not reached for other acoustic features, a pattern was observed that the Aβ‐positive group consistently displayed more medium pauses, longer audio duration, more local jitter, higher intensity variance, a higher fundamental frequency, and fewer long pauses in all multi‐day subtasks (Figure 1). Conclusion: Our results demonstrated that Aβ‐pathology was associated with more pauses during free speech in cognitively healthy adults. This supports the notion that remote multi‐day speech assessments have the potential to monitor cognitive changes, for example in observational studies and decentralized clinical trials in preclinical AD. Next steps include examining the association between Aβ‐pathology and linguistic features using the same sample. [ABSTRACT FROM AUTHOR]