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Objective: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer's Association (NIA-AA) research framework. Method: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. Results: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p <.001). Word List Delayed Recall (β = −.22, p <.05) and Trail Making Test (β = 6.2, p <.05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p <.001) and 4 (β = −2.23, p <.001). Conclusions: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD. [ABSTRACT FROM AUTHOR]

Introduction: Non‐pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. Methods: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. Results: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. Discussion: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area. [ABSTRACT FROM AUTHOR]

Background: Composite scores may be useful to summarize overall language or visuospatial functioning. We generated composite scores for these domains from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and evaluated their validity. Method: We used item response theory to derive composite measures for language (ADNI‐Lan) and visuospatial functioning (ADNI‐VS). We performed multiple validation analyses comparing ADNI‐Lan and ADNI‐VS to individual test and global scores among participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). We evaluated ability to detect change, strength of association with a priori selected structural brain imaging findings, association with risk of AD conversion for people with MCI, and differences in intercepts and slopes for people with MCI with vs. without the CSF AD biomarker signature. Result: There were 1,913 people with imaging data and age ³60. Single factor IRT models fit the data well for both composites. ADNI‐Lan outperformed MMSE language items, ADAS‐Cog language items, the Boston Naming Test (BNT), and fluency items in detecting change for MCI and AD. The clock score was modestly better than ADNI‐VS at detecting change for MCI and AD. ADNI Lan was the best at predicting MCI to AD conversion, while the clock score did slightly better than ADNI‐VS. Strength of association of language scores with structural MRI findings are shown in Table 1. ADNI‐Lan and the BNT had stronger associations than other scores for MCI in ADNI1, and also in ADNI2/ADNIGO except for BNT/temporal pole. For AD, ADNI‐Lan had strong associations with each region, similar to other scores except MMSE. Strength of association of visuospatial scores with structural MRI findings are shown in Table 2. ADNI‐VS and the clock had similar strong associations for most regions. People with MCI with the CSF AD biomarker signature had lower language intercepts, captured best by ADNI‐Lan, and more rapid decline, also captured best by ADNI‐Lan. Intercepts were not different for either visuospatial score, and ADNI‐VS and the clock score had similar slope terms. Conclusion: ADNI‐Lang and ADNI‐VS had good evidence of validity and may be useful composites for language and visuospatial functioning in ADNI. [ABSTRACT FROM AUTHOR]

Background: Identifying people with MCI at greatest risk of AD conversion is an important research goal. Our objective was to determine whether changes in domain‐specific cognitive functioning over 6 months could identify people at greatest risk of AD conversion. Method: We used modern psychometric methods applied to the ADNI cognitive battery to develop composite scores for memory, executive functioning, language, and visuospatial functioning. We considered scores at baseline and 6‐month visits for the 809 participants who had prevalent MCI in ADNI1, ADNIGO, and ADNI2, and characterized people based on quartiles of 6‐month changes in each domain. We used Cox models to determine whether 6‐month changes for each domain associated with risk for conversion to AD. We compared 6‐month changes to APOE genotype and the AD CSF biomarker signature, controlling for age, sex, and years of education. Result: 305 participants (38%) had zero bottom quartile change scores (most decline); 296 (37%) had one; 138 (17%) had two; 60 (7%) had three; and 10 (1.2%) had all four. Cox model results for 6‐month changes in all four domains without and with APOE genotype are shown in Table 1. There were 173 people with CSF results to characterize the AD biomarker signature. Cox results are shown in Table 2. Compared to people in the top quartile for 6‐month language change (most learning), people in the bottom quartile (most decline) were at increased risk of AD conversion, independent of APOE genotype and the AD biomarker signature. For 6‐month memory change, the hazard ratio for the bottom quartile (most decline) was attenuated when APOE genotype was included in the model, and it was null when the CSF biomarker signature was included. 6‐month changes in executive functioning and visuospatial functioning were not associated with risk of AD conversion. Conclusion: 6‐month changes in language identify people with MCI at highest risk of AD conversion. This effect is not explained by APOE genotype or CSF biomarkers. 6‐month language scores may identify people to target in AD prevention trials. [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.

Objective: To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is independent of mean RT performance., Method: N = 109 cognitively unimpaired individuals (age 77.4 ± 5.0, 61.5% female, Mini-Mental State Examination 29.1 ± 1.3) from the Harvard Aging Brain Study completed the self-administered Computerized Cognitive Composite (C3) monthly at home for up to 1 year (12.7 ± 3.2 C3 assessments). Baseline C3 assessment coincided with routine in-clinic visits, including amyloid and tau positron emission tomography imaging and standardized cognitive testing, with cognitive testing repeated annually (1.6 ± 1.2 years follow-up). The C3 includes two simple RT tasks and two complex RT tasks. IIV estimates were derived by computing intraindividual standard deviations on residual RT scores after regressing out age and session order effects. Cross-sectional associations of IIV with cognition (global cognition, memory, executive functions [EF], processing speed) and amyloid and tau burden were examined using linear regression analyses correcting for demographics and mean RT. The association between IIV and cognitive decline was assessed using linear mixed models correcting for demographic factors, mean RT, and amyloid burden., Results: After adjusting for mean RT, increased IIV on complex RT tasks was independently associated with worse EF performance (β = -0.10, 95% CI [-.16, -0.03], p = .004), greater inferior-temporal tau deposition (β = 0.18, 95% CI [0.02, 0.34], p = .024), and faster cognitive decline in those with elevated amyloid (β = -0.62, 95% CI [-1.18, -0.06], p = .033)., Conclusions: Increased variability in monthly RT may reflect subtle EF deficits and provide unique information about short-term cognitive decline in preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire., Method: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time., Results: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated ( r = -0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 ( SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [ B ] = -0.15, 95% confidence interval, 95% CI [-0.28, -0.03], effect size = -0.02), whereas CTT-based scores did not ( B = 0.20, 95% CI [-0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar., Conclusions: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Subjective cognitive decline (SCD) is defined as self-experienced, persistent concerns of decline in cognitive capacity in the context of normal performance on objective cognitive measures. Although SCD was initially thought to represent the "worried well," these concerns can be linked to subtle brain changes prior to changes in objective cognitive performance and, therefore, in some individuals, SCD may represent the early stages of an underlying neurodegenerative disease process (e.g., Alzheimer's disease). The field of SCD research has expanded rapidly over the years, and this review aims to provide an update on new advances in, and contributions to, the field of SCD in key areas and themes identified by researchers in this field as particularly important and impactful. First, we highlight recent studies examining sociodemographic and genetic risk factors for SCD, including explorations of SCD across racial and ethnic minoritized groups, and examinations of sex and gender considerations. Next, we review new findings on relationships between SCD and in vivo markers of pathophysiology, utilizing neuroimaging and biofluid data, as well as associations between SCD and objective cognitive tests and neuropsychiatric measures. Finally, we summarize recent work on interventions for SCD and areas of future growth in the field of SCD., Competing Interests: None of the authors (C.E.M, R.B., X.C., G.C., C.G., R.J.J., J.M., I.O., T.R., E.W., Y.T.Q., J.R.G., P.V., and R.A.) have any relevant disclosures or conflicts of interest. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: Dr. Weiner receives support for his work from the following funding sources: NIH: 5U19AG024904‐14; 1R01AG053798‐01A1; R01 MH098062; U24 AG057437‐01; 1U2CA060426‐01; 1R01AG058676‐01A1; and 1RF1AG059009‐01, DOD: W81XWH‐15‐2‐0070; 0W81XWH‐12‐2‐0012; W81XWH‐14‐1‐0462; W81XWH‐13‐1‐0259, PCORI: PPRN‐1501‐26817, California Dept. of Public Health: 16‐10054, U. Michigan: 18‐PAF01312, Siemens: 444951‐54249, Biogen: 174552, Hillblom Foundation: 2015‐A‐011‐NET, Alzheimer’s Association: BHR‐16‐459161; The State of California: 18‐109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, Fidelity Charitable, and the Veterans Administration. Dr. Weiner is a full time Professor for the University of California San Francisco (UCSF), and Principal Investigator of many projects with the above grant funding. Dr. Weiner has served on Advisory Boards for Cerecin/Accera, Alzheon, Inc., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Boston University Alzheimer’s Disease and CTE Center, MIRIADE at VUmc for Amsterdam UMC, Cytox, Indiana University, Acumen, Brain Health Registry and ADNI. He serves on the Editorial Boards for Alzheimer’s & Dementia, TMRI and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., Alzheimer’s Drug Discovery Foundation (ADDF), BioClinica, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California (USC), T3D Therapeutics, Cytox, and Japanese Organization for Medical Device Development, Inc. (JOMDD). He holds stock options with Alzheon, Inc., Alzeca, and Anven. D. Prins is consultant to Boehringer Ingelheim and Aribio. He is co‐PI of a study with Fuji Film Toyama Chemical. He serves on the DSMB of Abbvie’s M15‐566 trial. He is CEO and co‐owner of the Brain Research Center, The Netherlands. All other authors report no financial disclosures or conflicts of interest., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results., Methods: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System., Results: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols., Discussion: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Composite scores may be useful to summarize overall language or visuospatial functioning in studies of older adults., Methods: We used item response theory to derive composite measures for language (ADNI-Lan) and visuospatial functioning (ADNI-VS) from the cognitive battery administered in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We evaluated the scores among groups of people with normal cognition, mild cognitive impairment (MCI), and Alzheimer's disease (AD) in terms of responsiveness to change, association with imaging findings, and ability to differentiate between MCI participants who progressed to AD dementia and those who did not progress., Results: ADNI-Lan and ADNI-VS were able to detect change over time and predict conversion from MCI to AD. They were associated with most of the pre-specified magnetic resonance imaging measures. ADNI-Lan had strong associations with a cerebrospinal fluid biomarker pattern., Discussion: ADNI-Lan and ADNI-VS may be useful composites for language and visuospatial functioning in ADNI., Competing Interests: The authors declare that they have no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Practice effects (PEs) are improvements in performance after repeated exposure to test materials, and typically viewed as a source of bias in repeated cognitive assessments. We aimed to determine whether characterizing PEs could also provide a useful marker of early cognitive decline., Methods: We conducted a systematic review of the literature, searching PsycInfo (Ebsco) and PubMed databases for articles studying PEs in aging and dementia populations. Articles published between 1920 and 2019 were included., Result: We identified 259 articles, of which 27 studied PEs as markers of cognitive performance. These studies consistently showed that smaller, less-robust PEs were associated with current diagnostic status and/or future cognitive decline. In addition, lower PEs were associated with Alzheimer's disease risk factors and neurodegeneration biomarkers., Conclusion: PEs provide a potentially useful marker of cognitive decline, and could prove valuable as part of a cost-effective strategy to select individuals who are at-risk for dementia for future interventions., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC's sensitivity to decline in comparison to traditional clinical endpoints., Methods: This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment, or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6, and 12 months. Sensitivity to change was investigated using linear mixed models and r 2 effect sizes., Results: CFC scores declined over time ( β  = -.16, P <  .001), with steepest decline observed in mild Alzheimer's dementia ( β  = -.25, P <  .001). The CFC showed medium-to-large effect sizes at succeeding follow-up points ( r 2  = .08-.42), exhibiting greater change than the Clinical Dementia Rating scale ( r 2  = .02-.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline ( β  = .38, P  < .001)., Discussion: By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice., Competing Interests: R.J.J., A.B., R.V., R.A.J.D, F.J.J, C.W.R., E.O.M., and A.A. report no relevant disclosures. In the past 2 years, J.H. has received honoraria and paid consultancy from 23andMe, Abbvie, A2Q, AlzCure, Amgen, Anavex, Aptinyx, Astellas, AstraZeneca, Avraham, Axon, Axovant, Biogen, Boehringer Ingelheim, Bracket, Catenion, Cognition Therapeutics, CRF Health, Curasen, DeNDRoN, Enzymotec, Eisai, Eli Lilly, GfHEu, Heptares, Johnson & Johnson, Kaasa Health, Lysosome Therapeutics, Lundbeck, Merck, MyCognition, Mind Agilis, Neurocog, Neurim, Neuroscios, Neurotrack, Novartis, Nutricia, Pfizer, PriceSpective, Probiodrug, Regeneron, Rodin Therapeutics, Roche, Sanofi, Servier, Shire, Takeda, and vTv Therapeutics. P.S. has acquired grant support (for the institution) from GE Healthcare and Piramal. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Novartis, Probiodrug, Biogen, Roche, and EIP Pharma, LLC. S.A.M.S. is supported by grants from JPND and Zon‐MW, and has provided consultancy services in the past 2 years for Nutricia and Takeda. All funds were paid to her institution., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: To improve the detection of changes in Alzheimer's disease (AD), we designed the cognitive-functional composite (CFC). As a first validation step, we investigated its test-retest reliability and feasibility of use., Methods: We performed a test-retest study with 2-3 weeks between assessments, including patients with mild cognitive impairment (MCI) or mild AD dementia and cognitively healthy participants. We calculated intraclass correlation coefficients (ICCs) type absolute agreement for all CFC measures and compared baseline and retest scores using paired-samples t -tests. We evaluated feasibility by interviewing participants., Results: Forty-three patients (40% female, mean age = 69.9) and 30 controls (50% female, mean age = 65) were included. Subtest intraclass correlation coefficients ranged from .70 to .96. We found negligible improvements after retesting on only two subtests. Overall, patients perceived the administration of the CFC as feasible., Discussion: The CFC is a stable and feasible measure in MCI and mild AD dementia, and thereby meets important quality metrics for clinically meaningful outcome measures.