bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender Differences in the Association Between Subjective and Objective Cognitive Decline in a Diverse Cohort: LifeAfter90 Study
Authors: Chen Nancy X , Corrada María M. M. , Gilsanz Paola , Farias Sarah Tomaszewski , George Kristen M. , Posis Alexander Ivan B. , Meunier Claire C. , Lor Yi , Whitmer Rachel A.
Published: January 2025

Background

Few studies have investigated the relationship between subjective cognitive concerns and objective cognitive decline in the oldest‐old or examined gender differences. We evaluated this association and stratification by gender in a diverse cohort of adults ages 90+.

Methods

LifeAfter90 is an ongoing cohort of adults ages 90+. Verbal episodic memory (VEM) and executive function (EF) were assessed every 6‐months since 2018 using the Spanish and English Neuropsychological Assessment Scales. We operationalized subjective cognition two ways: 1) Dichotomously as yes/no via self‐report of subjective memory concerns (SMC)‐ “are you concerned that you have a memory or other thinking problem?”; 2) Continuously as degree of self‐rated changes in cognition using the 16‐item Everyday Cognition Scale (ECog). Linear mixed models with random intercepts and slopes estimated associations of SMC or ECog with VEM and EF at baseline and longitudinally, pooled and stratified by gender (female/male). Models adjusted for baseline age, gender (in pooled models), race/ethnicity, education, interview mode (in‐person or phone), and practice effects. Sensitivity models further stratified by SMC.

Results

Participants’ (N = 499) mean baseline age 93±2.4 years, mean follow‐up time 2.7±1.1 years, 62% women, 64% racial/ethnic minorities, 41% endorsed SMC, and mean ECog score 1.45±0.5. Overall, SMC and ECog were associated with worse baseline VEM (βSMC = ‐0.44,95%CI ‐0.61,‐0.27; βECog = ‐0.40,95%CI ‐0.58,‐0.22) and worse baseline EF (βSMC = ‐0.23,95%CI ‐0.39,‐0.07; βECog = ‐0.43,95%CI ‐0.59,‐0.27) (Table 2). ECog was associated with greater decline in EF (β = ‐0.05, 95%CI ‐0.10,0.00; Table 2). There were no gender differences in associations between SMC (p = 0.44) or ECog (p = 0.33) and VEM, nor ECog and EF (p = 0.76). The association between SMC and EF differed across genders (p = 0.01). In gender‐stratified models, both genders with SMC had worse baseline VEM and worse baseline EF, though not significantly for women (βmen = ‐0.54,95%CI ‐0.79,‐0.29; βwomen = ‐0.07,95%CI ‐0.27,0.13) (Table 2). Both genders with greater ECog had worse baseline VEM (βmen = ‐0.56,95%CI ‐0.87,‐0.26; βwomen = ‐0.33,95%CI ‐0.56,‐0.10) and worse baseline EF (βmen = ‐0.43,95%CI ‐0.70,‐0.14; βwomen = ‐0.41,95%CI ‐0.61,‐0.22) (Table 2). After stratification by SMC, among those with SMC, ECog was associated with worse baseline EF (β = ‐0.47,95%CI ‐0.68,‐0.26; Table 2).

Conclusion

In this diverse cohort of 90+, the association between subjective memory concerns and worse baseline EF was more pronounced in men than in women.
LUHMES Cells: In Vitro Model for Studying Tauopathy in Alzheimer’s Disease
Authors: Moffett Madeline , Parmar Mayur S
Published: January 2025

Background

Alzheimer’s disease (AD) is a common neurodegenerative disorder that results in the accumulation of amyloid‐beta, neurofibrillary tangles, and progressive cognitive decline. Despite extensive research into the pathophysiology of AD and potential treatments, a definitive cure remains elusive. Appropriate in vitro cell models are crucial for understanding pathophysiology and drug screening for AD. Cell lines like HEK293, HeLa, SH‐SY5Y, and PC have been used to study AD pathology. However, these models lack neuronal cell characteristics and do not express endogenous tau, a microtubule‐associated protein implicated in AD pathophysiology. The Lund Human Mesencephalic (LUHMES) cell line is a promising in vitro neuronal cell model that expresses endogenous tau protein, allowing a deeper exploration of tau pathophysiology and the assessment of biotherapeutics.

Method

The data was collected through the PubMed database. Review articles were selected based on the following keywords: “in vitro tauopathy,” “LUHMES and neurodegenerative disease,” “LUHMES and tauopathy,” “LUHMES and Alzheimer’s disease,” and “neuron cell line.” Articles utilized for the purpose of this study were primary research articles published in academic journals between 2014 and 2023.

Result

The LUHMES cell line is used to model known tauopathies, like AD and progressive supranuclear palsy (PSP), yet few studies have harnessed their potential. One study revealed that PP242, a dual inhibitor of mTORC1 and mTORC2, could reverse fenazaquin‐induced tau aggregation in LUHMES cells. Another study discovered that activating PERK, an endoplasmic reticulum stress sensor, reduced tau phosphorylation and aggregation in LUHMES cells. As human‐origin cells with neuronal properties, LUHMES cells provide an essential model for studying tau pathology in AD. The insights gathered from these LUHMES‐based studies highlight the utility and relevance of these cells in propelling our understanding of tauopathy forward.

Conclusion

The LUHMES are an important neuronal cell line that can be utilized for in vitro experiments to study tauopathy and evaluate biotherapeutics for their ability to modulate tau pathology. These cells have endogenous tau expression, a key characteristic differentiating this line from more commonly used cell lines, such as HEK293 and SH‐SY5Y. Significant progress toward evaluating effective treatments can be made by using the LUHMES cell line to study AD‐related tauopathy pathology.
Diverse genomic alterations in single neurons after chronic brain trauma
Authors: Miller Michael B , Ma Chanthia , Dong Guanlan , Naik Samuel , McDonough Gannon , Mao Shulin , McKee Ann C. , Huang August Yue , Lee Eunjung Alice , Walsh Christopher A
Published: January 2025

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impact (RHI) although little is known about its molecular pathogenesis. Previous studies of single neurons showed that private somatic mutations increase both during normal aging and in neurodegenerative disorders, and show diverse mutational patterns.

Method

We applied two orthogonal single‐nucleus whole‐genome sequencing (snWGS) methods to neurons isolated from the prefrontal cortex of 15 individuals with CTE, and 4 individuals with RHI but no CTE diagnosis, and compared mutational rates and spectra with neurons from neurotypical controls and Alzheimer’s disease (AD).

Result

We found a modest but significant elevation of somatic double‐stranded single‐nucleotide variants (SNVs) that resembles a pattern previously reported in AD. In addition, we found a strikingly large burden of small insertions and deletions (indels) and used duplex sequencing to show that these indels are mainly single‐stranded, and again found a similar phenomenon in neurons from AD brain.

Conclusion

Our results suggest that neurons in CTE brain are exposed to stereotyped mutational processes, and that these processes are shared between AD and CTE suggesting potentially shared pathogenic mechanisms. Furthermore, the absence of similar changes in RHI neurons without CTE suggests that the development of CTE entails a mechanism beyond that caused by RHI alone.
Differential effects of Apoe Christchurch (R136S) mutation on amyloid plaque and tau pathology in transgenic mouse models
Authors: Tran Kristine M , Kawauchi Shimako , Kwang Nellie , Mar Cassandra , Chao Donna , Da Cunha Celia , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N.
Published: January 2025

Background

A case study on a PSEN1 (E280A) carrier with APOECh (R136S) mutation revealed changes in APOE protein function led to a protective effect on AD outcomes. Notably, there is an intriguing disparity between the two hallmark pathologies: a reduction in tauopathy but no change in plaque burden. Given that the APOE protein is predominantly produced by astrocytes and activated microglia, and the APOE gene is among the disease‐associated microglia (DAM) genes, it is conceivable that the variance in pathological outcomes may be rooted in the glial response. Therefore, studying the APOEch mutation will provide a unique opportunity to investigate the role of APOE in tau and Aβ plaque development, with a particular emphasis on the proposed link: neuroinflammation.

Method

We used CRIPSR‐Cas9 to introduce ApoeCh into the mouse genome. Mice were then bred and crossed to homozygosity with the 5xFAD and PS19 transgenic mouse models to study the effect of the variant on amyloid plaque and tauopathy, respectively. Brain slices were immunolabeled for microglia and reactive astrocytes, and single‐cell spatial transcriptomics/proteomics was investigated using multiplexed error‐robust fluorescence in situ (MERFISH) technology. Plasma neurofilament light chain (NfL) along with Ab and tau protein levels were measured via MSD technology.

Result

In the 5xFAD mouse model, analysis of confocal images reveals reduction in plaque load in the 5xFAD mice at 12 months of age that is reflected in the global decrease in microglia and astrocyte number with ApoeCh. However, there is an increase in DAM response to plaque observed through elevated CD11c+ staining along with upregulation of DAM genes and protein levels via spatial transcriptomics and proteomics. In the PS19 mice, although there is an increase in phospho‐tau level, there is a stark reduction in microgliosis to tauopathy. Plasma neurofilament light chain levels reveal that ApoeCh reduces plasma NfL level in response to plaques but not tau.

Conclusion

ApoeCh mutation has differential effects on glial responses to plaque and tau. ApoeCh decreases plaque load and plasma NfL but increases inflammatory response to plaques. Whereas in a tau model, ApoeCh increases phosphorylated tau level but decreases microgliosis and inflammatory response to tau pathology.
ASSESSING DYNAMIC AFFECT RECOGNITION FOR DISTINGUISHING FRONTOTEMPORAL DEMENTIA SUBTYPES
Authors: Ulugut Hulya
Published: January 2025

Background

Recent international work suggests that more precise subtyping within frontotemporal dementia (FTD) syndromes leads to better prediction of pathology, supporting individualized disease‐specific treatments. Recent studies emphasize that identification of one such subtype, semantic behavioral variant FTD (sbvFTD), relies in part on measuring emotion recognition abilities.

Method

In order to evaluate the effectiveness of current tools, we compared the brief video‐based Dynamic Affect Recognition Test (DART) against the TASIT Emotion Evaluation (EET) and Comprehensive Affect Testing System Affect Matching tests. 105 individuals in the very early stages (CDR≤1) of FTD (61 behavioral variant FTD [bvFTD], 25 semantic variant primary progressive aphasia [svPPA], 19 sbvFTD), and 71 healthy older participants underwent emotion testing and structural MRI.

Result

Tests using dynamic (video) stimuli outperformed static face stimuli for distinguishing sbvFTD from bvFTD, but the DART outperformed the EET distinguishing sbvFTD from svPPA (Figure 1). Structural VBM analysis of DART performance showed predominant contribution of right‐sided structures involved in semantics and attention (e.g. temporal pole, insula), though in sbvFTD, who had worse DART scores than all other syndromes (p<0.05), DART performance also corresponded with temporo‐orbitofrontal structures mediating hedonic evaluation.

Conclusion

Our findings indicate that emotion reading tests using dynamic stimuli are best for differentiating among FTD syndromes. Also, unique profiles of emotion reading deficits emerging from different syndromes correspond to distinct patterns of damage to emotion, semantics, attention, and reward‐related brain networks. Emotion identification deficits are a core feature of FTD, therefore careful selection of tests that reflect the key underlying neural circuits will result in more accurate phenotyping.
Identifying the regulatory cascade governing amyloid precursor protein macropinocytosis and subsequent production of amyloid‐beta
Authors: Krupa Jordan M , Naqvi Abdul Moiz , Tsang Adrianna R , Seah Claudia , Pasternak Stephen H
Published: January 2025

Background

Previously, we identified macropinocytosis as a novel mechanism for direct and rapid trafficking of cell surface APP to lysosomes, bypassing early and late endosomes. This process depends on the activity of Arf6 and several Rho‐GTPases, and inhibition of macropinocytosis reduces amyloid‐beta (Aβ) production. Macropinocytosis is relatively unstudied in neurons and neuronal cells. Based on data from neuronal and non‐neuronal cell types, we hypothesized that the crosslinking of APP at the cell surface recruits Fe65, which acts as a scaffold for the recruitment and activation of Arf6. Arf6 then recruits the Rho‐GTPases Rac1, Cdc42 and RhoA, resulting in APP internalization by macropinocytosis and its cleavage to Aβ within the lysosome.

Methods

Neuro2a (N2a) neuronal cells or human IPSC‐derived primary cortical neurons were transduced with fluorescent‐tagged Fe65, Arf6, Rac1, Cdc42 or RhoA. Membrane PI(4,5)P2 was used to mark membrane ruffling using fluorescent‐tagged PLCδ‐PH. Live neuronal cells or neurons were incubated with anti‐APP antibodies on ice to crosslink cell surface APP. Cells were incubated at 37°C and imaged at specific time points using confocal microscopy and live cell imaging.

Result

Crosslinking APP resulted in rapid recruitment of Fe65 and Arf6 to APP and membrane ruffles within 30 sec, which rapidly decreased by 2 min. The Rho‐GTPases Rac1, Cdc42 and RhoA demonstrated sustained colocalization with APP and ruffles from 30 sec through to 2 min. This decreased at 5 and 10 min as APP was internalized. The inhibition of Arf6 using NAV2729 prevented the recruitment of itself, Rac1, Cdc42, and RhoA at 30 sec. However, inhibition of Rac1 by EHT 1864 had no significant effect on the recruitment of Rac1 to crosslinked APP.

Conclusion

These results demonstrate the sequential recruitment of regulatory proteins which regulate macropinocytosis of APP in response to its crosslinking. Fe65 and Arf6 are rapidly recruited to APP, followed by sustained recruitment of Rac1, RhoA and Cdc42. These regulatory proteins could be targeted to modulate APP‐lysosomal trafficking and reduce Aβ production.
Influence of ageing, cognitive factors, and task modality on social cognitive performance in nondemented older adults
Authors: Chander Russell J , Grainger Sarah A , Mather Karen A , Cleary Rhiagh , Kochan Nicole A. , Henry Julie D , Sachdev Perminder S.
Published: January 2025

Background

Social cognition is crucial to optimal social functioning outcomes in older adults, with implications for overall health and wellbeing. Moreover, poor social cognition is a diagnostic criterion for neurocognitive disorders (NCDs). Prior work has studied the social cognitive subdomains (theory of mind (ToM), affective empathy, emotion recognition, and social behaviour) and found mild cognitive impairment and dementia to be associated with poorer performance in specific tasks and informant‐reported changes respectively. These patterns in NCDs need to be distinguished from normal age‐related changes, and more information is needed to ascertain what factors predict social cognitive decline in healthy ageing.

Method

132 non‐demented participants [mean MMSE 29.23 (SD 0.99)] aged 60 to 100 underwent comprehensive social cognitive assessments that varied based on modality of information (Figure 1), alongside neurocognitive assessments and affective questionnaires. Participants were divided based on decades to study age‐related changes. Linear regression models identified significant predictors of social cognition performance amongst demographic, neuropsychological assessment scores, affective scores, and social networks.

Result

Age was associated with poorer performance in ToM tasks, specifically the Reading the Mind in the Eyes Test (RMET), Multifaceted Empathy Test (MET) Cognitive subscale, and The Awareness of Social Inference Test (TASIT) part 3, and emotion recognition tasks, specifically the FACES task and TASIT 1, for expressions of anger, disgust, and sadness (Table 1). In regression models (Table 2), age was a significant predictor of RMET and FACES performance. In MET cognitive and both TASITs, neuropsychological tasks, mainly executive function, were predictive. Poorer executive function predicted performance for identifying unspoken emotions (“Feel” subscore) in TASIT 3. MET Emotional and the self‐rated Interpersonal Reactivity Index (IRI) Empathic Concern subscale was associated with less anxiety and more positive emotions at assessment.

Conclusion

In ToM and emotion recognition, unimodal task performance was associated with age and some cognitive factors, and multimodal task performance was largely associated with executive function. Performance in affective empathy tasks was linked to affective measures. Poor performance in multimodal tasks likely reflects executive dysfunction in consolidating multiple streams of social information, while some declining performance in unimodal tasks may be normative to ageing.
FunGen‐xQTL atlas: a multi‐omic atlas of quantitative trait loci in human brain and cerebrospinal fluid for target identification and prioritization in Alzheimer’s disease
Authors: Leung Yuk Yee
Published: January 2025

Background

To gain a deeper understanding of underlying molecular mechanisms in genomic regions associated with Alzheimer’s disease (AD), the National Institute on Aging (NIA) launched the Alzheimer’s Disease Sequencing Project (ADSP) Functional Genomics Consortium (FunGen‐AD) in 2021.

Method

The first effort of this collaboration, coordinated by the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), aggregated functional genomics (FG) data from 5 cohorts, including ∼3,000 samples of European (EA) and African ancestries (AA). We used this data to map Quantitative Trait Loci (xQTL) on AD‐specific human tissues and cells, providing insights into how non‐coding genetic variants contribute to AD risk. We developed reproducible computational pipelines to uniformly process the data, generating xQTL from >30 datasets profiled from human brain, cerebrospinal fluid, myeloid cells, and whole blood. The genetic data was processed exactly as the ADSP WGS datasets (GRCh38, same variant/gene annotations). For each QTL dataset, performed quality control and imputed missing data, inferred hidden confounders, and conducted genome‐wide association testing for cis‐ and trans‐acting QTLs. We also performed statistical fine‐mapping to identify potential causal variants. The consolidated summary statistics contain effect alleles normalized to the GRCh38.

Result

Overall, this resource yielded >10 million cis‐ and trans‐QTL on DNA methylation, histone acetylation, RNA expression, RNA splicing, proteins, and metabolites. To support the identification of potential causal variants for molecular traits and AD, we have created a multi‐ancestry linkage disequilibrium reference panel using ADSP WGS data from >16,000 individuals of self‐reported EA and >5,000 individuals of self‐reported AA.

Beyond this unique FunGen‐xQTL atlas, other FG datasets generated by other non‐ADSP members are needed for AD genetics analyses. We developed the Harmonization and Integration Pipeline for Functional Genomics (hipFG) to harmonize all FunGen‐xQTL data together with other public resources such as GTEx, eQTL catalog, and metaBrain. Using controlled vocabularies, hipFG produces a standardized metadata describing all outputs. This pipeline is used to expand FILER (FunctIonaL gEnomics Repository), a framework for querying large‐scale genomics knowledge with a scalable genomic search and querying interface.

Conclusion

The FunGen‐xQTL resource will be made publicly available through Sage Bionetworks and NIAGADS.
Development of a composite score to predict Lewy body pathology burden
Authors: Choudhury Parichita , Chen Kewei , Zhang Nan , Tremblay Cécilia , Ho Andrew , Belden Christine , Adler Charles , Shill Holly , Mehta Shyamal , Driver‐Dunckley Erika , Shprecher David , Serrano Geidy E , Beach Thomas G. , Reiman Eric M. , Atri Alireza
Published: January 2025

Background

Lewy body (LB) diseases can present with overlapping prodromal, cognitive, motor, autonomic or neuropsychiatric symptoms. Intuitively, greater symptom severity should correlate with greater pathological burden, but this has not been consistently shown. LB pathology does not translate to clinical expression in Incidental LB disease. While several composite scores/toolkits utilize overlapping schemes for diagnosis, a composite data‐derived score to predict LB pathologic burden is lacking. We aimed to utilize an autopsy‐confirmed cohort, and validated, brief, and standardized clinical, functional, pathologic assessments, and machine learning (ML)/quantitative modeling techniques to identify clusters and importance rankings among assessments/measures to predict LB pathologic severity and density.

Method

A total of 234 subjects with neuropathological finding of LB at autopsy in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) who were classified as Cognitively Unimpaired or Mild Cognitive Impairment after their first study clinical evaluation were included. Of these, 145 subjects had complete scores for 32 of 46 measures (clinical, cognitive, behavioral and functional) that were utilized as predictors of LB pathology. Olfactory function was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). LB severity was assessed by the Unified Staging System for Lewy Body Disorders (USSLB). Several ML algorithms and quantitative prediction models were explored and compared: artificial neural network (ANN), partial least square regression (PLSR), support vector regression (SVR), relevance vector regression (RVR) and ensemble forest regression (EFR) with leave‐one‐out (LOO) scheme. Game‐theory based Shapley methods assessed the impact, including rankings, consistency and magnitude, of model predictors.

Result

RVR predicted aggregate LB density with large effect size (R2 = 0.691, p<0.00001). ANN predicted USSLB severity stage with large effect size (R2 = 0.74, p<2.5e‐43). All other ML algorithms/models provided substantial prediction. Across all models, UPSIT was the most influential predictor (>65%), followed by Controlled Oral Word Association Test (COWAT) and age.

Conclusion

These preliminary and exploratory results support the utilization of ML techniques/models to assess LB pathologic burden with key measures collected in relatively small samples. UPSIT was consistently ranked highest impactful among clinical and functional measures/predictors. Integrated together in ML/data‐derived composites, UPSIT, COWAT and other clinical characteristics may be of antemortem utility to predict USSLB stages.
Exploring relationships among neuropsychiatric symptoms, subjective cognitive complaints, cognitive performance, and incident dementia: Findings from the Sydney Memory and Ageing Study
Authors: Numbers Katya T. , Chander Russell J , Chen Jason , Brodaty Henry
Published: January 2025

Background

Subjective cognitive complaints (SCCs) and neuropsychiatric symptoms (NPS) are emerging as potential early indicators of neurodegenerative diseases like Alzheimer’s disease (AD). SCCs refers to a self‐perceived decline in cognitive abilities without objective impairment, while NPS describe neuropsychiatric symptoms that emerge in later life that may precede or co‐occur with cognitive decline. This study explores the association between SCCs, NPS, global cognition, and incident dementia using data from the Sydney Memory and Ageing Study (MAS).

Method

Participants were 754 older adults from MAS (M age = 78.76, SD = 4.71) with a diagnosis of normal cognition at baseline. SCC was determined based on participants reporting having noticed changes in their memory. NPS was defined as having scored >1 on the Neuropsychiatric Inventory (NPI) total score. Participants were categorised into four groups based on the presence of SCC and/or NPS. Outcome variables were global cognition (composite z‐score derived from tests of attention/processing speed, language, executive functions, visuospatial abilities, and memory) and clinical consensus diagnosis of dementia according to DSM‐IV criteria.

Result

Of the total participants, 217 (28.8%) had neither SCC nor NPS (SCC‐ NPS‐), 350 (46.4%) had SCC only (SCC+ NPS‐), 52 (6.9%) had NPS only (SCC‐ NPS+), and 236 had both SCC and NPS (NPS+SCC+). At baseline, SCC‐ NPS+ had significantly poorer global cognition than SCC‐ NPS‐ or SCC+ NPS‐. At wave 4 (6‐year follow‐up), SCC‐ NPS+ showed a steeper decline in global cognition compared to other groups. A greater proportion of SCC+ NPS+ at Wave 6 (10‐year follow‐up) had developed dementia compared to SCC‐ NPS‐. Multivariable logistic regression with age at baseline as the only covariate surviving stepwise elimination showed SCC‐ NPS+ (OR 3.70; SE 2.15; p = 0.025) and SCC+ NPS+ (OR 3.18; SE 1.25; p = 0.003) had increased odds over SCC‐ NPS‐ in developing dementia by Wave 6.

Conclusion

NPS is associated with poorer global cognition and, with or without SCC, is a significant long‐term risk factor for dementia. The findings highlight the potential importance of considering NPS alongside cognitive features, and suggest that assessing both neurobehavioral and neurocognitive dimensions could offer a more comprehensive risk assessment in cognitively normal individuals.
Progressive Dysexecutive Syndrome (PDS) due to Alzheimer’s Disease: Genetic and Neuroinflammatory Correlates in a Rapidly Progressive Case
Authors: Ritter Aaron , Brouwers Kaley , Kinney Jefferson W
Published: January 2025

Background

Many patients present to our clinic with primarily executive rather than amnestic impairments. Recently, Townley and colleagues proposed criteria for a progressive dysexecutive syndrome (PDS). To date, PDS has been reported to be more common in younger individuals (55‐65 years old) and is associated with Alzheimer’s biomarkers (AD). Less is known about the genetic and neuroinflammatory profile of patients with PDS.

Method

We report the clinical, biomarker, genetic, and autopsy data of a participant from the Center for Translational and Neuroscience (CNTN) meeting criteria for PDS.

Result

A 57‐year‐old left‐handed male presented with primary executive difficulties (bill paying, financial difficulties). Apathy was the only behavioral symptom reported. His initial neuropsychological testing showed impairments across a broad range of executive measures which worsened significantly over three years. Biomarker testing was consistent with Alzheimer’s disease (A+T+N+) with a significant elevation in plasma p‐tau 181 and neuroimaging showing peak involvement of the parietal lobes. Several plasma markers of neuroinflammation were elevated (GFAP, NFL) while others were depressed (IL‐6, IL‐10, TNF‐alpha). He was negative for autosomal dominant mutations (PS1, PS2, APP) but carried two apolipoprotein E4 genes (APOE 4/4) with an elevated polygenic risk score. Exome sequencing revealed polymorphisms within several known risk genes: CR1, PICALM, ABCA7. After experiencing a rapid cognitive decline, the participant died only five years after the onset of symptoms. Due to sparse neurofibillary tanges in the mesial temporal cortex he was characterized as having “hippocampal sparring” Alzheimer’s disease.

Conclusion

Progressive dysexecutive syndrome is a newly described variant of AD that affects younger individuals, causes impairments in executive functioning, and primarily impacts the fronto‐parietal networks. Findings from our case report suggest a possible neuroinflammatory susceptibility and multi‐factorial genetic basis.
Understanding the Interplay between Insulin Resistance and Cognitive Function: A Longitudinal study conducted in the Urban Cohort, Southern India
Authors: Menon Anjana J , S Monisha , Issac Thomas Gregor
Published: January 2025

Background

Recent epidemiological studies have shown that diabetes can have negative effects on cognitive function, and insulin resistance (IR) acts as a key factor in this association. IR can impede glucose uptake in brain, leading to energy deficits and toxic protein accumulation which may cause cognitive decline. Type 3 diabetes mellitus (T3DM), or AD type of diabetes is caused due to impaired insulin signalling restricted to brain regions, resulting in memory decline. This study therefore aims to explore the link between IR and cognitive dysfunction, which will help in understanding the role of IR as a potential risk factor of cognitive impairment.

Method

This study utilized 1007 participants aged 45 years and above, recruited by CBR‐Tata Longitudinal Study of Ageing (TLSA), which is a community‐based urban longitudinal study cohort. 569 participants were with IR, and 438 participants were healthy. Addenbrooke’s Cognitive Examination (ACE III) was utilised to assess cognitive performance of the participants and IR was measured using Homeostatic Model Assessment‐insulin resistance (HOMA‐IR). Mann Whitney U test was performed to compare between ACE scores and IR status. Further, Generalized Linear Model (GLM) analysis was performed between cognitive variables and IR status after adjusting for covariates.

Result

Mann Whitney U test showed a statistically significant association between IR status and ACE scores in ACE total, ACE attention and ACE visuospatial. GLM analysis revealed a significant negative correlation between IR status and performance in attention (B = ‐0.271, 95% CI (‐0.468, ‐0.073), p<0.05), as well as in visuospatial tasks (B = ‐0.258, 95% CI (‐0.494, ‐0.022), p<0.05). After adjusting for confounders such as age, education, and inflammatory marker like CRP, results showed that ACE attention scores (B = ‐0.396, 95% CI (‐0.396, ‐0.008), p<0.05) were significantly lower in participants with IR.

Conclusion

According to the findings of our study, insulin resistance was associated with poor cognitive outcome in the attention domain. This finding could be attributed to the increased sensitivity of prefrontal cortex to altered insulin levels. Thus, considering the association between IR and cognition, it is important to devise strategies that can help in detecting and treating IR at an early stage to prevent cognitive impairment.
Efficacy of brexpiprazole on frequently occurring agitation behaviors in patients with dementia due to Alzheimer’s disease: post hoc pooled analysis of two randomized controlled trials
Authors: Brubaker Malaak , Wang David , Chumki Sanjeda R , Such Pedro , Zhang Zhen , Palma Anton M
Published: January 2025

Background

Patients with dementia due to Alzheimer’s disease may experience multiple different agitation symptoms – including excessive motor activity, verbal aggression, and physical aggression – at varying frequencies. The efficacy of brexpiprazole 2 or 3 mg/day on 29 individual agitation behaviors (Cohen‐Mansfield Agitation Inventory [CMAI] items) was previously evaluated. Building upon that work, this post hoc analysis aimed to determine the efficacy of brexpiprazole on the same individual agitation behaviors, but specifically focusing on those patients who were frequently experiencing the behaviors at baseline.

Method

Data were included from two 12‐week, randomized, double‐blind, placebo‐controlled, parallel‐arm trials of fixed‐dose brexpiprazole in patients with agitation associated with dementia due to Alzheimer’s disease (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Efficacy was assessed using the CMAI, which measures the frequency of occurrence of 29 agitation behaviors (each scored 1 [never] to 7 [a few times an hour]). In this analysis, least squares mean change from baseline to Week 12 in each CMAI item score was determined in subsamples of patients for whom the corresponding behavior occurred at least once per week (item score ≥3) at baseline. Data for brexpiprazole 2 or 3 mg/day (FDA‐approved dose) and for placebo were pooled.

Result

Data were analyzed for 610 patients (brexpiprazole, n = 363; placebo, n = 247). At baseline, the mean (standard deviation) number of different agitation behaviors occurring at least weekly was 12.8 (4.3) per patient. The agitation behaviors most commonly occurring at least weekly were general restlessness (n = 572), pacing/aimless wandering (n = 513), and cursing or verbal aggression (n = 496). For some behaviors (e.g., intentional falling, n = 27), conclusions were limited by small subsample sizes. Across the CMAI items, least squares mean score changes from baseline to Week 12 ranged from ‐1.80 to ‐0.04 for brexpiprazole, and ‐1.34 to +0.84 for placebo, with a greater numerical reduction for brexpiprazole versus placebo on 24/29 items (Figure).

Conclusion

Patients with agitation associated with dementia due to Alzheimer’s disease exhibited many different frequently occurring agitation behaviors. Fixed‐dose brexpiprazole 2 or 3 mg/day was associated with a numerically greater reduction in the frequency of most of these frequently occurring agitation behaviors versus placebo.
Mild Behavioral Impairment association with the Visual Cognitive Assessment Test (VCAT) in a Southeast Asian Population with Vascular Mild Cognitive Impairment ‐ Biomarkers and Cognition Study, Singapore BIOCIS
Authors: Leow Yi Jin , Tanoto Pricilia , Vipin Ashwati , Azam Mohammed Adnan , Sandhu Gurveen Kaur , Lee Faith Phemie Hui En , Ghildiyal Smriti , Liew Shan Yao , Tan Isabelle Yu Zhen , Kandiah Nagaendran
Published: January 2025

Background

The Visual Cognitive Assessment Test (VCAT) is a visual based, language neutral cognitive assessment validated across cultures and ethnicities, that allows for early diagnosis of cognitive impairment. The VCAT assess domains of cognition – Memory, Visuospatial function, attention, language and Executive function. The Mild Behavioural Impairment Checklist (MBI‐C) was developed to assess five domains of NPS – Decreased motivation, emotional dysregulation, impulse control, social inappropriateness and abnormal beliefs/perceptions Current research indicates an association between MBI symptom severity and poorer cognitive performance in the domains of memory. We examined the association between mild behavioural impairment and domains of cognition as assessed by the VCAT in a multi‐ethnic Southeast Asian population.

Method

204 participants with vascular mild cognitive impairment (VMCI) were recruited from the community living in Singapore. VMIC was defined by Fazekas White Matter Hyperintensity(WMH) visual ratings of 4 and above. The mean age = 66.82 years, mean education = 13.54years with 39.8% males. Participants underwent neuropsychological assessments including the VCAT administered by trained raters and self‐reported questionnaires including the Mild Behavioural Impairment‐Checklist (MBI‐C).

Result

The VCAT‐Attention domain had a significant negative correlation with MBIC‐social subdomain (r = ‐0.276, p<0.05). With every 1 point increase in VCAT‐Attention. MBIC‐social subdomain decreased by 9% (estimate ‐0.357; 95% CI[0.516, 0.239]; p = 0.022).

Conclusion

Current research indicated that social isolation is one of the biggest risk factors for cognitive impairment, and our results reveal that social issues are associated with behavioural impairment as well. Attentional difficulties could lead to issues in inhibitory control, resulting in social inappropriateness. The V‐CAT’s ability to associate specific subdomains with MBI‐C subdomains suggest both tools could be a valuable tool for early detection and intervention in cognitive disorders.
A Data‐Driven Examination of Apathy and Depression in Cognitively Normal Older Adults
Authors: Da Silva Miguel Vasconcelos , Aarsland Dag , Ballard Clive G , Corbett Anne , Ismail Zahinoor , Creese Byron
Published: January 2025

Background

Apathy and mood symptoms are increasingly recognised as clinical important aspects of prodromal dementia; both are associated with increased risk of dementia even in cognitively normal people. The clinical overlap between apathy and low mood poses a challenge in distinguishing between the two conditions. It is crucial to differentiate between depression and apathy, along with any underlying syndromes, to facilitate the development of targeted treatments. Using a data‐driven approach, we recently reported the existence of distinct apathy and depression clusters in dementia, confirming observations from the clinic and epidemiology. In this study we sought to establish whether similar patterns of symptoms were present in cognitively normal older adults

Method

We analysed data from 21,925 community dwelling older adults. Latent class analysis (LCA) was applied to self‐reported and proxy ratings (obtained using the Mild Behavioral Impairment Checklist) of apathy and mood. Polygenic Risk Scores for Alzheimer’s disease (AD) and Major Depression (MDD) were tested for associated with class membership.

Result

The LCA analysis using proxy data showed a 4‐class group which was considered the best model: No symptoms, Depression, Apathy/depression, and an Apathy group. The LCA using self‐reported data reveals the 4‐class group without a as a clear apathy class as the proxy data (see Figures 1 and 2). PRS for AD and MDD were only associated with depression and apathy/depression classes in self‐reported data (not in proxy data).

Conclusion

This analysis highlights the apathy phenotype as a unique and separate condition, underscoring the imperative for additional research in this area. This emphasizes the potential for innovative approaches to delve deeper into the exploration and comprehension of apathy. The differences between the self and proxy reported data highlights the possibility of under reporting of apathy by patients.
Olfactory decline profiles and their association with dementia conversion in an older population with 12 years of follow‐up
Authors: Ekström Ingrid , Avelar‐Pereira Bárbara , Ruane Robert , Grande Giulia , Fratiglioni Laura , Larsson Maria , Laukka Erika J
Published: January 2025

Background

Olfactory impairment represents an early sensory marker of neurodegeneration, but little is known about how interindividual differences in the trajectories of olfactory change relate to dementia conversion. We aimed to characterize olfactory decline profiles during phases of normal cognition to assess their predictive value for dementia conversion.

Method

Olfactory trajectory profiles of dementia‐free persons (SNAC‐K; n = 1601; mean age = 70.0 years) were identified using growth mixture models (GMM) of repeated assessments with the Sniffin’ sticks odor identification task over 6 years of follow‐up. Olfactory functioning for old‐old participants (≥78 years) was assessed three times (at 3‐year‐interval), whereas young‐old participants (<78) were assessed twice (6‐year‐interval). Hazard ratio (HR) of dementia occurrence across 6 years after the olfactory trajectories were established was estimated with Cox regression. In total, participants were followed for up to 12 years.

Result

GMM analysis identified three distinct olfactory trajectory profiles. As opposed to the “maintained olfaction” profile (n = 952), the “decline” (n = 433) and “accelerated decline” (n = 216) profiles were characterized by lower olfactory ability at baseline, a more rapid decline over follow‐up, and were associated with increased hazard of dementia (HR: 1.82; 95% confidence interval [CI] 1.12‐2.96 for “decline” and HR: 3.55; 95% CI: 2.09‐6.02 for ”accelerated decline”). Sensitivity analyses identified two olfactory trajectory profiles for old‐old (i.e., maintain and decline) and four trajectory profiles for young‐old participants (i.e. maintain, decline, accelerated decline, and pronounced decline). Associations between low‐performing olfactory trajectory profiles and dementia were particularly strong in young‐old participants with “pronounced decline” (n = 66, HR: 9.52; 95% CI:2.54‐35.72).

Conclusion

We identified profiles based on olfactory decline trajectories in a sample that was initially cognitively normal. Participants with lower baseline olfaction and more rapid olfactory decline were grouped together, and these profiles were associated with an increased risk of developing dementia, as compared to participants who maintained their olfactory ability. Our results point towards a relatively early onset of dementia‐related olfactory decline. Intact olfactory ability in older age may indicate low risk of dementia conversion. As such longitudinal screening of olfaction may offer prognostic value.
Investigating mediating influences of β‐amyloid on the relationship between marital dissolution and cognition
Authors: Chandra Avinash , Anjum Rifah , Waters Sheena , Proitsi Petroula , Smith Laura J , Marshall Charles R
Published: January 2025

Background

Research has demonstrated that spousal loss through widowhood or divorce are associated with an increased risk of dementia and deteriorated cognitive performance. This is likely due to high levels of stress characteristic of these life events. Evidence suggests that neuropathology typically seen in Alzheimer’s disease, for example, β‐amyloid (Aβ), may be a by‐product of chronic stress. However, whether Aβ facilitates links between disruptive marital transitions and poor cognition remains unknown. The aim of the current study was to explore whether Aβ pathology could mediate associations between marital dissolution, either through divorce or widowhood, and domain‐specific cognitive performance in a cohort of cognitively normal (CN) subjects.

Method

Data was included for 543 participants in the Alzheimer’s Disease Neuroimaging Initiative classified as CN that had data on self‐reported marital status (married, divorced or widowed) and Aβ PET imaging. Aβ levels were quantified by Centiloid values. Cognitive performance data on executive functioning and episodic memory was available for all participants. Multiple linear regression was utilised for exploring inter‐relationships between marital dissolution, Aβ burden, and cognition, whilst follow‐up mediation analysis examined indirect effects of Aβ on the association between marital status and cognitive performance.

Results

Associations were found between elevated Aβ levels and both marital dissolution and poorer memory. Results from causal mediation analysis evidenced that Aβ was a significant mediator for the relationship between marital dissolution and episodic memory. These results were confirmed using the Baron and Kenney criteria for a partial mediation effect.

Conclusion

This study provides novel evidence that the accumulation of Aβ pathology in the brain may be a pathway through which the stress of marital dissolution acts on memory abilities. This may have further implications for dementia risk, but future research is needed. Findings highlight that interventions after spousal loss may be helpful for the preservation of brain health.
Cognitive performance in individuals aged 80 or over from south of Brazil
Authors: Budni Josiane , Keller Gabriela Serafim , Campos Ana Carolina Brunatto Falchetti , Medeiros Eduarda Behenck , Lídio Adrielly Vargas , Grings Luísa Rosler , Casagrande Débora Dagostin , De Jesus Laura Ceolin , Fenilli Gabriela Piovesan , Boaventura Amanda L , Zabot Gabriel Casagrande , Ceretta Luciane B
Published: January 2025

Background

The population aged 80 or over has increased, which may predispose people to dementia. Validated scales are used to diagnose them. The study aimed to compare cognitive evolution and associated factors in individuals aged 80 or over.

Method

The Research Ethics Committee from the University of Southern Santa Catarina (UNESC) authorized the study under 3,214,698. It was an observational, quantitative study with a cohort design. Individuals aged 80 or over were recruited for this study. One hundred twenty‐four participants were evaluated in 2016. After six years, they were reevaluated, with 102 participants lost to follow‐up, resulting in 22 participants for reapplication. In addition, 78 new participants entered the study, totaling 100 participants in 2022. Cognitive tests such as the Mini‐Mental State Examination (MMSE), Clock Test, Verbal Fluency, and Montreal Cognitive Assessment (MOCA) were applied.

Result

When comparing the two times, there was a significant difference in the percentage of retirement and participation in some activities in the community. Compared to cognitive tests, a decrease in cognitive decline and verbal fluency was observed in 2022, assessed by the MMSE. When the 22 individuals were evaluated over six years, there was a significant change in participation in community activities. When asked about difficulty remembering things, people, or situations, there was a reduction in 2022. Unlike the MMSE and the verbal fluency test, the MOCA showed cognitive impairment in most individuals in 2022.

Conclusion

It is concluded that the population of 2016 and 2022 showed some differences related to cognition, but this difference was not observed in the 22 individuals. These results indicate a divergence between the tests. Considering the many differences in the Brazilian population, it is necessary to standardize a cognitive test suitable for screening cognitive decline.
Exploring visual short‐term memory binding tests as early markers of cognitive decline: A comparative study between healthy aging and mild cognitive impairment
Authors: McAtarsney‐Kovacs Monika , Pardhan Shahina , Sapkota Raju , van der Linde Ian
Published: January 2025

Background

Elderly people, especially those with mild cognitive impairment (MCI), are at heightened risk of developing dementia. In this study, we examined how well healthy young, normally aging and MCI participants performed in visual short‐term memory (VSTM) binding, a cognitive process in which an item’s different visual properties (e.g., form, location, colour) are combined and stored momentarily in our mind before being forgotten. Earlier work has identified VSTM binding as a potential cognitive skill that may be disproportionately affected in those with MCI/dementia, meaning that it may serve as an early behavioral marker.

Method

Three groups of participants were recruited: 34 healthy young adults (mean age 25±3 years), 52 normally aging older adults (mean age 71±6.4 years) and 16 older adults with MCI (mean age 74±6years). All participants completed computer‐based VSTM tasks requiring the binding of object‐location, object name‐location, colour‐location, and colour word–location for two or four sequentially presented stimuli (presentation duration <1 sec). Participants also completed standard cognitive tests (Addenbrookes Cognitive Examination, Montreal Cognitive Assessment, Trail Making Test, National Adult Reading Test and CANTAB Paired Associates Learning). We compared the performance of healthy young and normally aging older groups to examine the effect of aging; normally aging older and MCI groups were compared to examine the effect of MCI.

Result

The performance of the normally aging older group was significantly lower than that of the healthy young group for memory tasks requiring object‐location (p = .003) and colour‐location (p = .014) binding. The performance of the MCI group was significantly lower than that of the normally aging older group for object name‐location (p = .014), colour‐location (p = .036) and colour word‐location (p<.001) VSTM tasks. VSTM binding performance correlated well with standard cognitive tests (ps ≤ .05).

Conclusion

The performance of the young healthy group exceeded that of both older groups. Not surprisingly the MCI group performed least well, particularly in tasks assessing object name‐location, colour‐location and colour word‐location binding. The disproportionate deterioration of these abilities implies that they may serve as early markers of the cognitive decline associated with MCI/dementia, and may form the basis of straightforward cognitive tests that may complement standard cognitive tests.