Early Cognitive Changes Research Articles

Cardiovascular risk of dementia is associated with brain–behaviour changes in cognitively healthy, middle-aged individuals

Alzheimer’s Disease (AD) neuropathology start decades before clinical manifestations, but whether risk factors are associated with early cognitive and brain changes in midlife remains poorly understood. We examined whether AD risk factors were associated with cognition and functional connectivity (FC) between the Locus Coeruleus (LC) and hippocampus – two key brain structures in AD neuropathology – cross-sectionally and longitudinally in cognitively healthy midlife individuals. Neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and FC with apolipoprotein ε4 (APOE ε4) genotype, family history of dementia, and the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score were investigated. Cross-sectionally, higher CAIDE scores were associated with worse cognition. Menopausal status interacted with the CAIDE risk on cognition. Furthermore, the CAIDE score significantly moderated the relationship between cognition and LC–Hippocampus FC. Longitudinally, the LC–Hippocampus FC decreased significantly over 2 years. These results suggest that cardiovascular risk of dementia is associated with brain–behaviour changes in cognitively healthy, middle-aged individuals.

Cognitive Outcomes in Autosomal-Dominant Alzheimer's Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation.

The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

Evaluating cognitive assessment tools for patients with major depressive disorder receiving electroconvulsive therapy: A systematic review and meta-analysis

BackgroundMajor Depressive Disorder (MDD) affects 350 million people worldwide. Electroconvulsive therapy (ECT) is effective, yet research on cognitive assessments post-treatment is lacking. This study systematically reviews and meta-analyzes the effectiveness of cognitive assessment tools post-ECT to optimize MDD treatment. MethodsFollowing PRISMA guidelines, this review was pre-registered on PROSPERO (CRD42023470318). Searches were conducted across nine databases up to November 12, 2023. Quality assessment for Randomized Controlled Trials (RCTs) and quasi-experimental studies was performed using the Cochrane risk of bias tool, JBI critical appraisal tools, and the Jadad scale. Meta-analyses for short-term and long-term cognitive function involved 24 and 18 tools, respectively. FindingsThirty studies (20 RCTs and 10 quasi-experimental) involving 2462 MDD patients were evaluated. Results indicated no significant differences in overall short-term and long-term cognitive functions post-ECT. Short-term analysis showed impairments in memory, learning, and verbal abilities but improvements in attention and processing speed. Long-term analysis revealed enhancements in memory, learning, verbal, and visuospatial abilities compared to baseline. Based on GRADE classification, we recommend 11 tools for assessing acute cognitive function and 10 tools for chronic cognitive impairment. These tools demonstrated high reliability and validity, supporting their clinical use. InterpretationThese findings provide critical evidence for future ECT clinical guidelines in managing MDD. The recommended tools can aid clinicians in adjusting ECT regimens, identifying early cognitive changes, and improving therapeutic outcomes in MDD treatment.

The Inflammasome Adaptor Protein ASC in Plasma as a Biomarker of Early Cognitive Changes.

Dementia is a group of symptoms including memory loss, language difficulties, and other types of cognitive and functional impairments that affects 57 million people worldwide, with the incidence expected to double by 2040. Therefore, there is an unmet need to develop reliable biomarkers to diagnose early brain impairments so that emerging interventions can be applied before brain degeneration. Here, we performed biomarker analyses for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β 42/40 (Aβ42/40) ratio in the plasma of older adults. Participants had blood drawn at baseline and underwent two annual clinical and cognitive evaluations. The groups tested either cognitively normal on both evaluations (NN), cognitively normal year 1 but cognitively impaired year 2 (NI), or cognitively impaired on both evaluations (II). ASC was elevated in the plasma of the NI group compared to the NN and II groups. Additionally, Aβ42 was increased in the plasma in the NI and II groups compared to the NN group. Importantly, the area under the curve (AUC) for ASC in participants older than 70 years old in NN vs. NI groups was 0.81, indicating that ASC is a promising plasma biomarker for early detection of cognitive decline.

The memory binding test in a longitudinal study of cognitive aging and preclinical disease.

The Memory Binding Test (MBT) shows promise in detecting early cognitive changes associated with Alzheimer's disease (AD). This study assesses the psychometric properties (i.e., construct and criterion validity, test-retest reliability) of the MBT and its sensitivity to incipient disease and incident cognitive impairment. One hundred forty-nine cognitively unimpaired adults ages 45-85 completed the MBT and neuropsychological tests at baseline; 132 returned for 2-year follow-up. Based on neuroradiological ratings of amyloid positron emission tomography and MRI markers at baseline, they were categorized as healthy (n = 94) or having preclinical disease (n = 55, either on the AD continuum or having non-AD pathologic change). Construct validity was assessed by the associations between MBT scores, demographics, and neuropsychological scores within the healthy group. Criterion validity was assessed by testing how MBT scores correlate with AD biomarkers, differ and discriminate between groups at baseline, and predict incident cognitive impairment. MBT scores decreased with age and were strongly associated with memory and global cognition. MBT scores were largely not associated with amyloid, hippocampal volume, or AD signature cortical volume but related to white matter lesion volume in those with preclinical disease. The preclinical groups performed worse on MBT immediate free recall at baseline than the healthy group, but no scores predicted incident cognitive impairment at follow-up. Most scores demonstrated modest test-retest reliability. This study demonstrates that the MBT has adequate construct validity in cognitively unimpaired adults, moderate sensitivity to preclinical disease cross-sectionally, and limited prognostic utility. Careful consideration of demographic influences on score interpretation remains necessary. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Increased intraindividual variability (IIV) in reaction time is the earliest indicator of cognitive change in MS: A two-year observational study

BackgroundCognitive decline in multiple sclerosis (MS) is common, but unpredictable, and increases with disease duration. As such, early detection of cognitive decline may improve the effectiveness of interventions. To that end, the Symbol Digit Modalities Test (SDMT) is effective in detecting slow processing speed as it relates to cognitive impairment, and intraindividual variability (IIV) observed in trials assessing continuous reaction time (RT) may be a useful indicator of early cognitive changes. Here, we will assess cognitive IIV changes in adults with early MS. MethodsAdults with relapsing-remitting MS (RRMS), <11 years since diagnosis, were recruited nationally. Baseline and two-year follow-up assessments included Brief International Cognitive Assessment in MS (BICAMS) and Cogstate computerized tests. Intraindividual variability in RT was calculated from psychomotor tasks and data were age-normalized. ResultsA total of 44 of the 66 participants completed follow-up (mean age, 34.0 ± 5.5 years; 66 % female; mean disease duration, 4.1 ± 2.9 years; median Expanded Disability Status Scale (EDSS) score, 1.5 [0 to 6.0]). Participants were grouped by SDMT z-score median split. Groups did not differ in demographics or clinical features. The higher baseline SDMT group was faster (p = 0.05) in RT and less variable (lower IIV, p = 0.001). At the two-year follow-up, the higher SDMT group showed increased variability (p = 0.05) compared to the lower SDMT group, with no significant RT or BICAMS changes. ConclusionsIn early MS, higher SDMT performance at baseline is associated with less cognitive variability but may indicate susceptibility to increased variability over time, highlighting the importance of monitoring IIV for early cognitive changes.

Cultural adaptation of the brain health assessment for early detection of cognitive impairment in Southeast Nigeria.

The aging population in developing countries demands parallel improvements in brain health assessment services to mitigate stigma, promote healthy aging, and diagnose cognitive impairments including dementia in primary health care (PHC) facilities. The lack of culturally appropriate cognitive assessment tools in PHC facilities delays early detection. This study aims to culturally adapt a brief digital cognitive assessment tool for PHC professionals in Southeast Nigeria. A total of 30 participants (15 healthcare workers HCW and 15 community members) were selected to be culturally representative of the community. We completed focus groups and pilot testing to evaluate and refine the Brain Health Assessment (BHA) a subset of tools from the Tablet-based Cognitive Assessment Tool (TabCAT) known to be sensitive to cognitive impairment in other settings. We examined BHA subtests across local languages (Pidgin and Igbo) spoken at two geriatric clinics in Anambra State Southeast Nigeria. Following structured approaches in focus groups, adaptations were made to the Favorites (memory) and Line Length (visuospatial) subtests based on their input. Participants found the new adaptations to have good construct validity for the region. The BHA subtests showed content validity for future work needed to validate the tool for detecting early cognitive changes associated with dementia and Alzheimer's disease in PHC settings. The use of culturally adapted and concise digital cognitive assessment tools relevant to healthcare professionals in Southeast Nigeria's PHCs is advocated.

Neuropsychological Assessment for Early Detection and Diagnosis of Dementia: Current Knowledge and New Insights.

Dementia remains an underdiagnosed syndrome, and there is a need to improve the early detection of cognitive decline. This narrative review examines the role of neuropsychological assessment in the characterization of cognitive changes associated with dementia syndrome at different states. The first section describes the early indicators of cognitive decline and the major barriers to their identification. Further, the optimal cognitive screening conditions and the most widely accepted tests are described. The second section analyzes the main differences in cognitive performance between Alzheimer's disease and other subtypes of dementia. Finally, the current challenges of neuropsychological assessment in aging/dementia and future approaches are discussed. Essentially, we find that current research is beginning to uncover early cognitive changes that precede dementia, while continuing to improve and refine the differential diagnosis of neurodegenerative disorders that cause dementia. However, neuropsychology faces several barriers, including the cultural diversity of the populations, a limited implementation in public health systems, and the adaptation to technological advances. Nowadays, neuropsychological assessment plays a fundamental role in characterizing cognitive decline in the different stages of dementia, but more efforts are needed to develop harmonized procedures that facilitate its use in different clinical contexts and research protocols.

Online cognitive monitoring technology for people with Parkinson’s disease and REM sleep behavioural disorder

Automated online cognitive assessments are set to revolutionise clinical research and healthcare. However, their applicability for Parkinson’s Disease (PD) and REM Sleep Behavioural Disorder (RBD), a strong PD precursor, is underexplored. Here, we developed an online battery to measure early cognitive changes in PD and RBD. Evaluating 19 candidate tasks showed significant global accuracy deficits in PD (0.65 SD, p = 0.003) and RBD (0.45 SD, p = 0.027), driven by memory, language, attention and executive underperformance, and global reaction time deficits in PD (0.61 SD, p = 0.001). We identified a brief 20-min battery that had sensitivity to deficits across these cognitive domains while being robust to the device used. This battery was more sensitive to early-stage and prodromal deficits than the supervised neuropsychological scales. It also diverged from those scales, capturing additional cognitive factors sensitive to PD and RBD. This technology offers an economical and scalable method for assessing these populations that can complement standard supervised practices.

Characterizing cognitive profiles in diverse middle-aged and older Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging (HCHS/SOL).

We investigated cognitive profiles among diverse, middle-aged and older Hispanic/Latino adults in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) cohort using a cross-sectional observational study design. Based on weighted descriptive statistics, the average baseline age of the target population was 56.4 years, slightly more than half were women (54.6%), and 38.4% reported less than a high school education. We used latent profile analysis of demographically adjusted z scores on SOL-INCA neurocognitive tests spanning domains of verbal memory, language, processing speed, and executive function. Statistical fit assessment indices combined with clinical interpretation suggested five profiles: (1) a Higher Global group performing in the average-to-high-average range across all cognitive and instrumental activity of daily living (IADL) tests (13.8%); (2) a Higher Memory group with relatively high performance on memory tests but average performance across all other cognitive/IADL tests (24.6%); (3) a Lower Memory group with relatively low performance on memory tests but average performance across all other cognitive/IADL tests (32.8%); (4) a Lower Executive Function group with relatively low performance on executive function and processing speed tests but average-to-low-average performance across all other cognitive/IADL tests (16.6%); and (5) a Lower Global group performing low-average-to-mildly impaired across all cognitive/IADL tests (12.1%). Our results provide evidence of heterogeneity in the cognitive profiles of a representative, community-dwelling sample of diverse Hispanic/Latino adults. Our analyses yielded cognitive profiles that may assist efforts to better understand the early cognitive changes that may portend Alzheimer's disease and related dementias among diverse Hispanics/Latinos. The present study characterized cognitive profiles among diverse middle-aged and older Hispanic/Latino adults.Latent profile analysis of neurocognitive test scores was the primary analysis conducted.The target population consists of middle-aged and older Hispanic/Latino adults enrolled in the Hispanic Community Health Study/Study of Latinos and ancillary Study of Latinos - Investigation of Neurocognitive Aging.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease

Background and purposeA substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. MethodsThirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). ResultsStatistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = −0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. ConclusionThis cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.

Performance on the Latin American version of the Face-Name Associative Memory Exam (LAS-FNAME) distinguishes individuals with Mild Cognitive Impairment from age-matched controls in a sample from Argentina

Introduction The Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) has shown promise in identifying cognitive changes in those at risk for Alzheimer’s disease (AD). However, its applicability for Mild Cognitive Impairment (MCI) detection in the Latin American population remains unexplored. This study aims to analyze the psychometric properties in terms of validity and reliability and diagnostic performance of the LAS-FNAME for the detection of memory disorders in patients with amnestic MCI (aMCI). Materials and methods The study included 31 participants with aMCI, diagnosed by a neurologist according to Petersen’s criteria, and 19 healthy controls. Inclusion criteria for the aMCI group were to be 60 years of age or older, report cognitive complaints, have a memory test score (Craft Story 21) below a -1.5 z-score and have preserved functioning in activities of daily living. Participants completed LAS-FNAME and a comprehensive neuropsychological assessment. Results LAS-FNAME showed the ability to discriminate against healthy controls from patients with aMCI (AUC= 75) in comparison with a gold-standard memory test (AUC = 69.1). LAS-FNAME also showed evidence of concurrent and divergent validity with a standard memory test (RAVLT) (r = 0.58, p < .001) and with an attention task (Digit Span) (r = −0.37, p = .06). Finally, the reliability index was very high (α = 0.88). Discussion LAS-FNAME effectively distinguished aMCI patients from healthy controls, suggesting its potential for detecting early cognitive changes in Alzheimer’s prodromal stages among Spanish speakers.

Visuo-Cognitive Phenotypes in Early Multiple Sclerosis: A Multisystem Model of Visual Processing

Background: Cognitive impairment can emerge in the earliest stages of multiple sclerosis (MS), with heterogeneity in cognitive deficits often hindering symptom identification and management. Sensory–motor dysfunction, such as visual processing impairment, is also common in early disease and can impact neuropsychological task performance in MS. However, cognitive phenotype research in MS does not currently consider the relationship between early cognitive changes and visual processing impairment. Objectives: This study explored the relationship between cognition and visual processing in early MS by adopting a three-system model of afferent sensory, central cognitive and efferent ocular motor visual processing to identify distinct visuo-cognitive phenotypes. Methods: Patients with clinically isolated syndrome and relapsing–remitting MS underwent neuro-ophthalmic, ocular motor and neuropsychological evaluation to assess each visual processing system. The factor structure of ocular motor variables was examined using exploratory factor analysis, and phenotypes were identified using latent profile analysis. Results: Analyses revealed three ocular-motor constructs (cognitive control, cognitive processing speed and basic visual processing) and four visuo-cognitive phenotypes (early visual changes, efferent-cognitive, cognitive control and afferent-processing speed). While the efferent-cognitive phenotype was present in significantly older patients than was the early visual changes phenotype, there were no other demographic differences between phenotypes. The efferent-cognitive and cognitive control phenotypes had poorer performance on the Symbol Digit Modalities Test compared to that of other phenotypes; however, no other differences in performance were detected. Conclusion: Our findings suggest that distinct visual processing deficits in early MS may differentially impact cognition, which is not captured using standard neuropsychological evaluation. Further research may facilitate improved symptom identification and intervention in early disease.

Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes.

In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: β=2.44, p<0.001, M7: β=2.57, p<0.001) and executive function performance (M4: β=-2.00, p=0.005, M7: β=-2.39, p<0.001). In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

Spatiotemporal Correlation between Amyloid and Tau Accumulations Underlies Cognitive Changes in Aging.

It is poorly known how Aβ and tau accumulations associate at the spatiotemporal level in the in vivo human brain to impact cognitive changes in older adults prior to AD symptoms onset. In this study, we used a graph theory-based spatiotemporal analysis to characterize the cortical patterns of Aβ and tau deposits and their relationship with cognitive changes in the Harvard Aging Brain Study (HABS) cohort. We found that the temporal accumulations of interlinked Aβ and tau pathology display distinctive spatiotemporal correlations associated with early cognitive decline. Notably, we observed that baseline Aβ deposits-Thal amyloid phase Ⅱ-related to future increase of tau deposits, Braak stages Ⅰ-Ⅳ, both displaying linkage to the decline in multi-domain cognitive scores. We also found unimodal tau-to-tau and cognitive impairment associations in broad areas of Braak stages Ⅰ-Ⅳ. The unimodal Aβ-to-Aβ progressions were not associated with cognitive changes. Our results revealed a multifaceted correlation of the spatiotemporal Aβ and tau associations with cognitive decline over time, in which tau-to-tau and tau-Aβ interactions, and not Aβ independently, might be critical contributors to clinical trajectories toward AD in older adults.

Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing.

This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. At the cross-section, there were no statistically significant differences in performance between Aβ+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517.

In-vehicle Sensing and Data Analysis for Older Drivers with Mild Cognitive Impairment.

Driving is a complex daily activity indicating age and disease-related cognitive declines. Therefore, deficits in driving performance compared with ones without mild cognitive impairment (MCI) can reflect changes in cognitive functioning. There is increasing evidence that unobtrusive monitoring of older adults' driving performance in a daily-life setting may allow us to detect subtle early changes in cognition. The objectives of this paper include designing low-cost in-vehicle sensing hardware capable of obtaining high-precision positioning and telematics data, identifying important indicators for early changes in cognition, and detecting early-warning signs of cognitive impairment in a truly normal, day-to-day driving condition with machine learning approaches. Our statistical analysis comparing drivers with MCI to those without reveals that those with MCI exhibit smoother and safer driving patterns. This suggests that drivers with MCI are cognizant of their condition and tend to avoid erratic driving behaviors. Furthermore, our Random Forest models identified the number of night trips, number of trips, and education as the most influential factors in our data evaluation.

Utility of Cognitive Abilities Screening Instrument (CASI) subscores in detecting early impairment in autosomal dominant Alzheimer’s disease (ADAD)

AbstractBackgroundPrior research among patients with autosomal dominant Alzheimer’s Disease (ADAD) has identified early cognitive changes 10‐20 years before formal dementia diagnosis. ADAD provides a model of Alzheimer’s disease (AD) with a relatively predictable onset and with fewer age‐related comorbidities, and as such, may aid in identifying presymptomatic stages of cognitive change for early AD detection. The CASI is a comprehensive screening tool for dementia with multilingual adaptations and may be useful in identifying early cognitive changes among those with or at risk of ADAD.MethodWe examined whether subscales of the Cognitive Abilities Screening Instrument (CASI) could identify early cognitive changes in ADAD as well as the effects of test language (English or Spanish), education, and acculturation on CASI subscales. 141 persons (96 mutation carriers [MC], 45 noncarriers [NC]) with or at risk for inheriting PSEN1/2 or APP mutations completed the CASI. Linear mixed‐effect models were used to examine the effects of adjusted age, mutation status, mutation type (APP or PSEN), test language, education, and acculturation on the 9 CASI subscales.ResultMCs performed significantly worse on CASI subscales than NCs (ps&lt;.001). Adjusted age (βs = ‐.29— ‐.09), mutation status (βs = ‐2.62—‐0.09), and adjusted age x mutation status (βs = ‐.29— ‐0.09) significantly predicted Attention (R2 = 0.36), Concentration (R2 = 0.40), Orientation (R2 = 0.53), Short‐Term Memory (R2 = 0.61), Long‐Term Memory (R2 = 0.27), Language (R2 = 0.39), Visuoconstruction (R2 = 0.53), Fluency (R2 = 0.34), and Abstraction/Judgment (R2 = 0.37), all ps &lt;.001. Acculturation significantly predicted Long‐Term Memory (β = .34, p = .03). The effects of acculturation, test language, and education were not significant for any other CASI subscales.ConclusionAdjusted age, mutation status, and an interactive effect between adjusted age and mutation status appear to be important predictors in CASI performance, such that MCs closer to their familial age of dementia diagnosis are more likely to perform worse on the CASI. No subtest emerged as the best predictor of early cognitive changes in MCs. Attention to potential cultural influences on the Long‐Term Memory subtest warrants further research.

Clinical Manifestations.

In Alzheimer's disease (AD), a long preclinical and prodromal period precedes dementia onset in which cognition declines slowly, but at variable rates for different domains. Positive AD biomarkers, (e.g., amyloid, Tau, or APOE ε4 carriage), increase rates of cognitive decline and transition to dementia. However, the extent to which cognitive decline, identified in some older adults, reflects neurodegenerative disease or normal aging in the absence of knowledge about biomarkers or genes is not well understood. We applied a novel approach to classify cognitive decline in individuals using six cognitive composite scores (AIBL Pre-clinical Alzheimer's Cognitive Composite (AIBL-PACC), episodic recall, attention, executive function, language and recognition). We examine group-wise differences across cognitive composite scores and assessed frequencies for AD biomarker positivity amongst the novel groups. Prospective data from 1,389 Cognitively unimpaired (CU) participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were analysed using an unsupervised multivariate mixture modelling framework, accounting for age, gender and APOE ε4 allele status. Participants cognitive status was classified for their final visit. The cognitive profile and biomarker characteristics of adults with abnormal cognitive decline was compared. Differences in composite score values between cognitive decline and no decline groups were strongest for episodic recall (Cohen's d = 1.49) and the AIBL-PACC score (Cohen's d = 1.45, Table 1, Figure 1A). By comparison, differences in composite scores between Aβ-PET groups, or APOE ε4 allele carriers/non-carriers were of less magnitude (Table 1, Figure 1). Participants with cognitive decline were more likely to be amyloid positive, (decline: 42% vs no decline: 28%, p<0.0001), but not ε4 allele carriers (decline: 28% VS no decline: 27%, p>0.05). A measure of objective cognitive decline, created using flexible mixture models with six cognitive composite scores from AIBL, has utility for discerning participants with early changes in cognition. Based upon using the cognitive data alone, this method was able to detect amyloid positivity in those CU participants with cognitive decline.

Associations between NIH‐Toolbox Flanker test and the Picture Sequence Memory Test and multimodal Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundAlzheimer’s disease (AD) pathologic changes start years before cognitive symptoms appear; however, some early cognitive changes can be detected. We aimed to investigate the association between performance changes in two NIH‐Toolbox tests, Flanker test and Picture Sequence Memory Test (PSMT), and baseline AD biomarkers in cognitively unimpaired (CU) individuals.MethodWe studied 356 ALFA+ participants (mean [SD] age = 60.8 [4.72] years). The rate of cognitive change after 3 years was measured through delta scores (Follow‐up ‐ Baseline). Biomarker data included cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio, phosphorylated‐tau‐181 (p‐tau), neurofilament light (NfL), and neuroimaging (MRI‐based cortical thickness AD signature, hippocampal volumes, and FDG‐PET‐SUVR (fluorodeoxyglucose ‐ positron emission tomography ‐ standardized uptake value ratio) metaROI) measures (Table 1). CSF Aβ40, Aβ42 and NfL were measured with the exploratory NTK robust immunoassays, while CSF p‐tau181 was measured using the electrochemiluminescence Elecsys® Phospho‐Tau (181P) CSF immunoassays (Roche Diagnostics International Ltd). AT groups were defined according to published cut‐offs (A+ Aβ 42/40 &lt;0.071; T+: p‐tau &gt; 24 pg/ml) (Milà‐Alomà et al., 2020). Baseline biomarker levels were used as predictors of cognitive change in linear models. Interactions and stratified analyses were also explored.ResultAT groups significantly differed in the change in the Flanker Test (p = 0.002), driven by poorer performance in A+T+ vs A‐T‐ groups (p = 0.001) (Figure1). Higher cortical thickness predicted better longitudinal cognitive performance in the Flanker Test in the whole group (p = 0.020; β = 0.983). We found a significant interaction between AT group and FDG‐PET‐SUVR (p = 0.042), and the right hippocampal volume (p = 0.001), but no significant associations were observed in analyses stratified by AT (Figure2A). A negative association between right hippocampal volume and Flanker test change was observed in A+T‐ (p = 0.026) and A+T+ (p = 0.029) (Figure2B). No associations were observed between the PSMT and AD biomarkers (Figure 1).ConclusionOur findings support the hypothesis that executive function show a steeper decline than episodic memory in CU individuals with evidence of pathologic AD biomarkers levels. We observed a negative association between executive change and neuroimaging neurodegeneration markers in A+T‐ and A+T+ groups. This is in accordance with previous studies that found non‐linear associations in incipient AD pathology.