bluuebunny/crossref_metadata_2025 huggingface dataset:
Incremental validity of the Test of Practical Judgment
Authors: Premnath Pranitha Y , Nester Caroline O , Krishnan Anjali , Pare Nadia , Wilhelm Anna F , Zatkalik Abigail L , Warren David E , Rabin Laura
Published: January 2025

Background

Judgment is an aspect of executive functioning that is critical to many aspects of daily functioning, and often affected in older adults with cognitive decline. The Test of Practical Judgement (TOP‐J) evaluates judgment related real‐world issues that may arise in aging populations. The current study investigates the incremental validity of the TOP‐J—i.e., the degree to which the TOP‐J adds unique and meaningful information to a clinical assessment beyond other executive functioning tests which are often used as proxies for judgment.

Methods

Participants (N = 97, Mage = 74.73; 74.2%female) who were classified as cognitively unimpaired (CU), subjective cognitive decline (SCD), or mild cognitive impairment (MCI) completed comprehensive neuropsychological evaluation, which included the Wisconsin Card Sorting Test (64‐card version) and Delis‐Kaplan Executive Function System tests of Verbal Fluency and Trail Making Test, Condition 4. Incremental validity was assessed through hierarchical linear regression analysis and was measured by the addition of the TOP‐J (Forms A, B, a composite of A + B), above these widely used executive functioning tests, with clinical diagnosis (CU, SCD and MCI) as the outcome.

Results

The addition of the TOP‐J A was statistically significant (R2 = .299, F(1,90) = 3.95, p = 0.05) and added incremental validity to predict diagnosis (∆R2 = .031, p = 0.05). The addition of the TOP‐J forms A + B composite also was significant (R2 = .307, F(1,90) = 4.99, p = 0.03, and added incremental validity(∆R2 = .038, p = 0.03), while the TOP‐J B trended toward significance (∆R2 = .024, p = 0.08).

Conclusion

Our results suggest that including the TOP‐J within neuropsychological evaluations of older adults can enhance diagnostic accuracy and provide clinically valuable information beyond what is derived from traditional executive functioning tests. Considering potential adverse impacts of impaired judgement abilities in the context of neurodegenerative disease, it is of utmost importance to improve the detection of diminished practical judgment skills to increase the protection of vulnerable populations and to prevent potential financial, social, and other areas of exploitation that may occur.
Influence of behavioral and psychological symptoms on caregiver burden for different types of dementia: clinical experience in Lima, Peru
Authors: Montesinos Rosa , Custodio Belen , Malaga Marco , Chambergo‐Michilot Diego , Verastegui Graciet , Agüero‐Flores Katherine , Alejos‐Zirena Juan , Andamayo‐Villalba Luis , Seminario G Wendy , Custodio Nilton
Published: January 2025

Background

People caring of individuals with dementia are prone to suffering from burden. Behavioral and psychological symptoms of dementia (BPSD) may have an impact on caregiver burden. In Latin American countries there is lack of research on caregiver burden. We aimed to determine which BPSD have the greatest impact on caregiver burden among Peruvian patients with dementia; and to compare the effects of BPSD on caregiver burden across different types of dementia.

Methods

Cross‐sectional study of 231 patients living with Alzheimer’s dementia (AD), behavioral variant frontotemporal dementia (bvFTD), dementia with Lewy bodies (DLB) and vascular dementia (VD), and their caregivers attended in a Peruvian memory clinic. BPSD were assessed with the Neuropsychiatric Inventory (NPI). Caregiver burden was assessed with the Zarit Burden Inventory (ZBI). We used analysis of variance to compare the groups of AD, bvFTD, DLB and VD. Correlations between ZBI and NPI subscale scores were assessed with Spearman’s correlation.

Results

DLB caregivers had significantly higher levels of burden than the other patient groups (P < 0.05), and higher total NPI scores than caregivers for other patient groups (P < 0.05). bvFTD caregivers had significantly higher total NPI scores than AD and VD caregivers (P < 0.05). Hallucinations, aberrant motor behavior, and apathy were the symptoms most significantly correlated with caregiver burden in those caring for DLB, bvFTD, and AD patients, respectively.

Conclusions

Neuropsychiatric symptoms are higher in DLB caregivers. Hallucinations, aberrant motor behavior, and apathy are the main symptoms correlated with burden.
Review of the MMSE as a Pre‐Screening Tool for Dementia in Clinical Trials
Authors: Voccia Pamela , Fundora Noel , Jones Cyntauria , Thomas Sheniba Pennyfeather , Boateng‐Poku Andrew , Otekalu Olumide
Published: January 2025

Background

The Mini Mental State Exam (MMSE) is a widely used prescreening tool in dementia research.

Method

Psychometric Raters from two sites within the Alcanza Clinical Research network collected MMSE data from 85 potential subjects who presented for memory trials. Subjects were later screened for Alzheimer’s Dementia studies, and the results from subsequent administrations of the Clinical Dementia Rating scale were available for 53 of those subjects.

Result

All 85 prescreening subjects endorsed memory concerns as the primary complaint. However, 56% (n = 48) scored within the Normal Cognition range (25‐30) on the MMSE.

Comparisons were made between some of the MMSE total scores and the calculated Global scores on subsequent administrations of the Clinical Dementia Rating scale (n = 53). The Clinical Dementia Rating Scale (CDR) is a semi‐structured clinical interview involving self‐report of memory, caregiver reports and clinician observations of cognition. The CDR is widely considered to be a reliable measure of the presence of symptoms related to dementia.

The range of the total MMSE scores for 53 subjects later evaluated with the CDR was between 18 and 28. Of those, all 53 (100%) were revealed to have symptoms of dementia based on CDR scores (CDR 0.5‐2), even though 33% of those patients had scored within the Normal range on the MMSE (25‐30; N = 18).

The average MMSE score for subjects falling within the Very Mild Dementia range (CDR = 0.5) was 23.9 with a standard deviation of 2.5 (n = 41). Of the subjects falling within this range, 41% scored within the Normal range on the MMSE (MMSE = 25‐28).

The average MMSE score for subjects falling within the Mild to Moderate Dementia range (CDR 1 or 2) was 21.2, with a standard deviation of 2.9 (n = 12). Of the subjects falling within this range, 1 patient (8%) scored within the Normal Range on the MMSE (MMSE = 26).

Conclusion

Based on this limited analysis, it appears that using the MMSE alone as a screener for dementia may result in missing up to 33% of symptomatic patients. Within these sample groups, the initial self‐endorsement of memory concerns was a more reliable predictor of CDR outcomes than the MMSE.
Early identification of participants at risk of cognitive decline: An online tool for patient prediction of cognitive decline
Authors: Cespedes Marcela Ines , Canovas Rodrigo , Gillis Cai , Maserejian Nancy N , Maruff Paul , Fowler Christopher J , Rainey‐Smith Stephanie R , Martins Ralph N , Masters Colin L , Doecke James D. ,   The ADOPIC Consortium
Published: January 2025

Background

The success of therapeutic options for treatment of Alzheimer’s disease (AD) and the growing emphasis for such treatment to commence in the pre‐clinical phase makes it necessary to have robust empirical models of clinical disease progression to understand findings from clinical trials, allow clinicians to evaluate effects of new drugs, and to select individuals for future trials. Such models have been developed from relatively small samples, with incomplete data/substantial loss to follow‐up. The ADOPIC consortium provides the largest complete AD natural history sample to date. We applied our sigmoid models of disease progression to cognitive data from ADOPIC, and developed an algorithm to predict cognitive change.

Method

We developed an online application (Prediction of Alzheimer’s Disease Progression Tool, [PADPT]) to estimate decline in cognition over the course of AD within 2,861 ADOPIC participants (1,434 Cognitively unimpaired [CU], 342 MCI [Mild Cognitive Impairment], 211 AD, and 847 progressed from CU→MCI or MCI→AD), with ≥1 PET Amyloid (Aβ) scan and ≥36 months of cognitive assessment with the pre‐clinical Alzheimer’s cognitive composite (PACC). Individual participant slopes were defined according to age and gender using linear mixed effects models. Aβ+ (≥50CL) participant rates of decline vs their mean PACC score were investigated using quantile polynomial regression. Within PADPT, single visit information on age, clinical classification and APOE ε4 allele status is entered to compute the estimated annual rate of decline. Candidate results are mapped to the sigmoid curve to determine their predicted rate of cognitive decline over the chosen time period.

Result

Quantile regression bands (QRB’s) aligned with participant cognitive decline. Individuals with stable cognition clustered to the top right of the plot (Figure 1). Mean slopes for APOE ε4 allele status separated QRB’s for CU and AD, but not for MCI groups. All participants allocated to cognitive decline groups (past the first sigmoid inflection point) demonstrated decline in PACC score that remained in the QRB’s, regardless of initial clinical classification.

Conclusion

Used in conjunction with baseline profile information, the PADPT application can assist with clinical decision making both pre and post‐treatment and also identify suitable clinical trial candidates who, untreated, will show subtle decline in cognition.
Sex differences in the relationship between physical activity and cognition as mediated by leukocyte telomere length: a UK Biobank study
Authors: Ortega Nancy E , Aslanyan Vahan , Pa Judy
Published: January 2025

Background

Evaluating sex differences in modifiable risk factors for Alzheimer’s disease could provide valuable information regarding the mechanisms by which these factors confer risk. Physical activity is a risk factor that has been shown to positively impact both telomere length, a marker of cellular age, and cognition. The goal of this study was to evaluate whether telomere length mediates the association between physical activity and cognition differently by sex.

Method

Participants from the UK Biobank were included in the sample based on availability of demographic variables, physical activity questionnaires, leukocyte telomere length, and cognitive measurements (Fluid Intelligence (FI), Numeric Memory (NM), Reaction Time (RT)). Metabolic Equivalent Task (MET) scores were derived from self‐report questionnaires following the International Physical Activity Questionnaire (IPAQ) guidelines. Relative leukocyte telomere length was measured by quantitative PCR and adjusted for technical variation by the UK Biobank. The indirect effect of physical activity on cognition via telomere length was evaluated using causal mediation analyses in R. Models were adjusted for age, body mass index, and Townsend Deprivation Index (Figure 1). A priori sex‐stratified models were used to examine sex differences.

Result

The sample included 374,761 adults (52.2% women, mean age±SD = 56.3±8.12 years, see Table 1). Linear regression analyses identified negative associations between weekly physical activity measures (i.e., summed MET minutes of all activity p<0.05*, MET minutes of moderate activity p<0.001***) and telomere length in men. This negative relationship was similarly found in women (MET minutes of walking p<0.05*), except for MET minutes of vigorous activity where a positive relationship with telomere length was observed (p<0.05*). In men, telomere length mediated the relationship between MET minutes of moderate activity and FI scores (p<0.001***), whereas in women this was only seen for walking (p = 0.04*). The association between vigorous activity and performance on the NM task was mediated by telomere length in women only (p = 0.04*). Lastly, telomere length mediated the relationship between RT performance and summed minutes of all activity in men only (p<0.001***).

Conclusion

Telomere length mediates the relationship between physical activity and cognition differently in men and women based on the intensity level of the physical activity.
Usefulness of The Test of Practical Judgement for the detection of MCI in a Southeast Asian Population
Authors: Tanoto Pricilia , Leow Yi Jin , Ghildiyal Smriti , Lee Faith Phemie Hui En , Liew Shan Yao , Tan Isabelle Yu Zhen , Chong Wayne Freeman , Seah Eunice Limin , Azam Mohammed Adnan , Vipin Ashwati , Sandhu Gurveen Kaur , Zailan Fatin Zahra , Tan Farid Tan Bin Hasyim , Kandiah Nagaendran
Published: January 2025

Background

The Test of Practical Judgement (TOP‐J) in its 9‐item (TOPJ9) and 15‐item (TOPJ15) versions (Rabin et el., 2007), validated for assessing practical judgement, encompasses day‐to‐day scenarios in medical, financial, safety, and social/ethical domains. This study seeks to evaluate its utility in distinguishing cognitively unimpaired (CU) individuals from those with Mild Cognitive Impairment (MCI) within a Southeast Asian population. This investigation aims to contribute insights into the cross‐cultural applicability of TOP‐J in assessing practical judgement across varying cognitive states in the Southeast Asian context.

Method

A cohort of 126 non‐demented participants from the Biomarker and Cognition Study, Singapore (BIOCIS) database underwent a comprehensive neuropsychological assessment, including TOPJ9, TOPJ15, Visual Cognitive Assessment Test (VCAT), Weschler Memory Scale (WMS‐IV) Logical Memory Story Delayed Recall, and Rey Auditory Verbal Learning Test (RAVLT) delayed test in a single session. MCI was diagnosed using the Petersen criteria (Petersen et al., 2001). Additionally, mean scores for neuropsychological tests were compared. Receiver Operating Characteristic (ROC) curve was used to assess the discriminative performance of TOP‐J between CU and MCI groups. Two‐by‐two tables facilitated the calculation of test sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) for each test.

Result

The mean age of the 126 participants were 60.34 years ± 9.64, 38% male, mean education of 15.16 years ± 3.11, and 82% Chinese ethnicity. Significant mean differences between groups were observed for each test (p<0.05) (Table 1). ROC Analysis indicated optimal cut‐offs for MCI identification were determined for TOPJ9 (<16.5, AUC = 0.76, Sn = 0.71, Sp = 0.7, PPV = 0.57, NPV = 0.81) and TOPJ15 (<25.5, AUC = 0.79, Sn = 0.55, Sp = 0.9, PPV = 0.75, NPV = 0.78). Discriminative properties with story delayed and RAVLT delayed are detailed in Table 2.

Conclusion

Both TOP‐J 9 and 15 items are useful for the detection of MCI in a Southeast Asian population. They exhibit comparable efficacy with other neuropsychological tests for MCI detection in Southeast Asian participants. Further validation through a longitudinal study is essential to solidify their diagnostic utility in this population.
Exploring PACC5 Associations with Cortical Thickness in Individuals with Subjective Cognitive Decline
Authors: Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Solé‐Padullés Cristina , Cabello‐Toscano María , Perera‐Cruz Oriol , Abellaneda‐Pérez Kilian , Cattaneo Gabriele , Sánchez Javier Solana , Alviarez‐Schulze Vanessa , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: January 2025

Background

Individuals with subjective cognitive decline (SCD) express concern about self‐perceived cognitive decline, despite no objective impairment, and are at higher risk of developing Alzheimer’s disease (AD). The preclinical Alzheimer’s cognitive composite (PACC5) is a sensitive cognitive marker frequently used in preclinical AD, delineating cognitive trajectories based on amyloid status in SCD. The relationship between PACC5 and brain structure remains unexplored. We aimed to study whether PACC5 associations with brain structure in an SCD group differ from those in a control group.

Method

Six hundred sixteen participants from the Barcelona Brain Health Initiative cohort (https://bbhi.cat/en) underwent magnetic resonance imaging acquisition and neuropsychological assessment. Among them, 89 healthy participants (56.18±7.72 years, 61 females) met the SCD criteria (memory concerns within the last 2 years). Meanwhile, 89 non‐SCD participants were age, sex, and educationally matched as the control group. PACC5 included z‐scores from dementia screening, episodic memory, processing speed, and category fluency tests. Cortical thickness (CTh) maps were generated with Freesurfer using T1‐ and T2‐weighted images. Whole‐brain vertex‐wise general linear models were employed and adjusted by age, sex, and educational level.

Result

The SCD group showed a trend toward lower PACC5 scores (W = 4569.5, p = 0.055; Figure 1a) and a significantly thinner cortex in the right middle and inferior temporal (CWP = 0.00898; Figure 1b). Examining PACC5‐CTh associations, group interactions emerged in four clusters (Figure 2a): the left posterior cingulate cortex (CC) and precuneus (CWP = 0.005), the left rostral anterior CC and superior frontal (CWP = 0.012), and the left and right post‐central cortex (CWP = 0.019, 0.001, respectively). Separate examinations uncovered a positive association in the right post‐central and superior parietal exclusively for the SCD group (CWP = 0.001; Figure 2b).

Conclusion

Adults with SCD trend toward a lower PACC5, presenting a reduced temporal CTh, an early atrophied region reported in neurodegenerative disorders, compared to the controls. Thinner left anterior and posterior CC and precuneus contributed to the lower PACC5 in SCD compared to controls. These results are relevant, as the CC role in resilience processes for cognitive impairment in AD is proposed, an aspect underexplored in SCD.
Natural language processing‐based analysis of connected speech in prodromal Alzheimer’s disease
Authors: Balabin Helena , Spruyt Laure , Eycken Ella , Kabouche Ines , Tamm Bastiaan , Schaeverbeke Jolien , Dupont Patrick , Moens Marie‐Francine , Vandenberghe Rik
Published: January 2025

Background

Connected speech has been explored as a possible marker for Alzheimer’s disease (AD) by employing language models based on machine learning. However, most previous approaches are based on scene description tasks, and it is unclear how different types of connected speech and differences across subjects’ speech relate to changes in their brains.

Method

We analyzed transcripts of Flemish Dutch connected speech from interviews from 74 cognitively healthy elderly adults (mean MMSE = 28.71 [25‐30], age = 73.15 years, 40 female) and 27 prodromal AD patients (mean MMSE = 25.22 [20‐30], age = 71.64 years, 13 female) across five parts: an autobiography, descriptions of a recent day, a news event, a set of nouns and the Cookie Theft scene. In the noun description task, subjects were asked to explain 10 abstract and 10 concrete nouns in detail. Using the Dutch RobBERT language model, we derived speech‐based representations for each interview part and subject, and first differentiated the two groups by fine‐tuning RobBERT with a classification layer. Then, we linked speech‐based features from the best performing task and structural MRIs for 99 subjects. Normalized gray matter volumes were processed using the Brainnetome atlas, resulting in 246‐dimensional subject representations, separated by regions. Distance matrices across subjects for speech‐ and MRI‐based representations were correlated in a representational similarity analysis (RSA), yielding Spearman correlations for each brain region.

Result

For the classification task (see Table 1), all interview parts exceeded the majority class baseline accuracy of 0.733, except for the scene descriptions. The noun descriptions resulted in the highest accuracy (0.795) and specificity (0.947) across the interview parts. Overall, classification yielded high specificity but low sensitivity. Further, the RSA correlation between the subjects’ noun descriptions and their gray matter volumes can be mainly attributed to the hippocampus, fusiform gyrus (FuG) and superior temporal gyrus (STG) (see Figure 1).

Conclusion

Connected speech elicited by scene description tasks reveal low accuracy and sensitivity for automated natural language processing‐based detection of prodromal AD. Noun descriptions could emerge as a viable alternative, demonstrated by their improved classification performance and link to brain regions relevant for memory and language.
Demographic Correlates of Visuo‐Cognition in a Healthy Ageing Indian Population ‐ A Cross‐Sectional Analysis
Authors: Vishwanath Vindhya , Malo Palash K. , Partha Ajith , M Divya N , Lingegodwa Abhishek Mensegere , Stezin Albert , M Amitha C , Narayanasamy Rajitha , Menon Meenakshi , R Meghana , Velavarajan Goutham , HS Deva Kumar , Arvind Prathima , S Monisha , Hameed Shafeeq K Shahul , HS Sunitha , Agrawal Deepashri , Mondal Banashree , Singh Sadhana , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Visuo‐cognitive skills represent a network of different abilities that rely on vision and cognition. While visuo‐cognitive abilities have been considered prominent indicators of dementia, there is a dearth of studies that profile these abilities with demographic correlates in an aging Indian population. Investigating the pattern of visuo‐cognitive abilities is essential to facilitate early indication, better prognosis and treatment of symptoms.

Method

The sample comprises baseline data collected from 1271 urban aging individuals (≥ 45 years) who are a part of the Tata Longitudinal Study on Ageing (TLSA), Bangalore, India. Visuo‐cognition was measured by Visuospatial span (VS), Visual Attention (VA), Modified Taylor Complex Figure (MTCF) Copy, Immediate Recall (IR), Delayed Recall (DR), and the visuospatial domain from Addenbrooke’s Cognitive Examination (ACE) III. Unadjusted effect was performed using Mann Whitney U and adjustments were made using General Linear Model to examine the association between each visuo‐cognitive test and demographic factors.

Result

In the total sample of 1271 participants, there were 620 females and 651 males. Mean age of females and males is 60.2±8.68 & 63.69 ±9.61 respectively. Mean years of education in females was 14.36 with a standard deviation of ±3.92. Mean years of education in males was 15.33 with a standard deviation of ±4.07. The correlation between age and MTCF Copy Time was positive, whereas with visuospatial span, visual attention, MTCF Copy, MTCF DR, and visuospatial domain of ACE III age was negatively correlated. Females performed better on tests of VA, MTCF IR, and the visuospatial domain on ACE III. There was a positive correlation between education and visuospatial span, visual attention, MTCF Copy, IR, DR, and visuospatial domain of ACE III. A negative correlation was found between education and MTCF Copy time and no significant association of the variables with MTCF IR Time.

Conclusion

Age and education influenced various visuo‐cognitive components, while gender had specific impacts on visual attention and MTCF measures. These findings provide insights for early diagnosis, tailored interventions, and further investigations into cognitive health.
Language and Cognitive Control in Aging Urban and Rural Cohorts in India
Authors: Menon Meenakshi , Malo Palash K , Lingegodwa Abhishek Mensegere , Stezin Albert , Hameed Shafeeq K Shahul , Narayanasamy Rajitha , Vishwanath Vindhya , R Meghana , M Divya N , Partha Ajith , M Amitha C , HS Dev Kumar , Arvind Prathima , Agrawal Deepashri , HS Sunitha , Velavarajan Goutham , Mondal Banashree , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Cognitive control deficits can be early indicators of cognitive decline in individuals. Studies have found a bilingual advantage in cognitive control, however, there is little research on the Indian population, particularly those residing in rural areas. We aimed to investigate how cognitive control is influenced by the number of languages known to individuals among the aging population in both urban and rural settings in South India.

Method

The study comprises cross‐sectional data from healthy individuals aged 45 years and above, with 1058 participants from the urban Tata Longitudinal Study on Ageing (CBR‐TLSA) cohort and 4820 participants from the rural Srinivaspura Ageing, Neuro Senescence, and Cognition (CBR‐SANSCOG) study cohort. Both study protocols are harmonized. Cognitive control was assessed using the Stroop, visuospatial span, categorical fluency, and letter fluency tests. Mann‐Whitney U test was used to compare monolingual and multilingual participants’ performance in cognitive control tasks separately. The differences in monolingualism and multilingualism on cognitive control were adjusted with age, gender, years of education, cohort, and Hamilton Depression Rating Scale (Ham‐D) scores using the General Linear Model.

Result

Urban participants performed better than their rural counterparts in all four cognitive control tasks (Table 1). Within the urban cohort, multilingual participants’ performed better than the monolingual participants in the categorical fluency task, whereas, in the rural cohort, multilingual participants performed better in all four tasks. Monolingual and multilingual participants in the urban cohort performed better than their respective counterparts in the rural cohort in the cognitive control tasks. After adjusting for the covariates, we found a significant difference between monolingual and multilingual participants on the categorical fluency task, with multilingual participants performing better than monolinguals (Table 2).

Conclusion

Our results indicated a multilingual advantage in cognitive control in aging Indians.
Assessing the impact of physical activity on cognitive function among urban elderly population: a cross‐sectional analysis
Authors: HS Deva Kumar , Selva Monisha , Lingegodwa Abhishek Mensegere , Stezin Albert , Partha Ajith , Mallikarjun Divya N , M Amitha C , Narayanasamy Rajitha , Menon Meenakshi , R Meghana , Vishwanath Vindhya , Velavarajan Goutham , Malo Palash K , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Evidence from multiple converging sources has demonstrated the clear benefits of physical activity in promoting mental health and improving cognitive function. However, more than 54% of Indians do not engage in the recommended amount of physical activity. The present study aims to explore the association of physical activity with cognitive abilities among the elderly aging population in an urban Indian setting.

Methods

The study utilized baseline data of 1250 till Dec 2023 from the ongoing Tata Longitudinal Study of Ageing cohort study. We categorized subjects into physically active (PA) and sedentary groups (SG)based on the time they spend doing different types of physical activity in a typical week using the Global Physical Activity Questionnaire (GPAQ). Cognitive assessments were performed using Addenbrooke’s Cognitive Examination III (ACE‐III). Multiple linear regression was performed where cog variables were loaded as dependent variables, physical activity was a predictor, and covariates used were education, gender, socioeconomic status, and clinical dementia rating scores.

Result

The mean age SD) of the study sample was 62.6 (9.6) years. Among 1250 participants, 804 (64.3%) were physically active and 446 (35.7%) belonged to the sedentary group. The physically active group had significantly higher median years of education (14.9 vs 14.6; p = <0.001), more proportion of males (56.3% vs 43.5%, p < 0.001), upper socioeconomic class (62.8% vs 34.2%) and lesser people with mild cognitive impairment (6.1% vs 14.2, p <0.001) as shown in Table 1. Multiple linear regression analysis shows that after controlling for confounding variables, the physically active group performed better in ACE total (β = ‐1.330, p = 0.002), ACE memory (β = ‐0.627, p < 0.001), ACE fluency (β = ‐0.257, p = 0.043) and ACE language (β = ‐0.263, p = 0.012) when compared to the sedentary group as shown in Table 2. ACE attention and ACE visuospatial scores were not statistically significant between both groups.

Conclusion

Our findings indicate that physically active participants had better global cognition and better performance in memory, executive functioning, and perceptual‐motor function. Promotion of physical activity should hence be implemented for enhancing cognitive abilities in elderly individuals.
Similar brain proteomic signatures in Alzheimer’s disease and epilepsy
Authors: Leitner Dominique , Pires Geoffrey , Kavanagh Tomas , Kanshin Evgeny , Askenazi Manor , Ueberheide Beatrix , Devinsky Orrin , Drummond Eleanor , Wisniewski Thomas
Published: January 2025

Background

Prevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment is common among people with epilepsy, with seizures occurring in 10‐22% of AD patients, subclinical epileptiform abnormalities in 22‐54% of AD patients, and cognitive deficits in up to 80% of epilepsy patients. These shared pathophysiological changes remain poorly defined.

Methods

We aimed to identify protein differences associated with epilepsy and AD using published proteomics datasets, including our previous analysis in epilepsy hippocampus and from our searchable database of 38 AD proteomics studies (NeuroPro). Additionally, laser capture microdissection was performed in dual diagnosed (AD+epilepsy) cases, epilepsy, AD, and control cases in hippocampal CA1‐3 (n = 7/group), followed by label‐free quantitative mass spectrometry to identify protein differences.

Results

We observed a significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau. This suggests tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for amyloid‐beta and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. To better understand mechanisms of epilepsy in AD, we performed localized proteomics in the hippocampal CA1‐3 of dual diagnosed cases. We observed protein changes compared to controls (275 proteins), with fewer differences than either AD (67) or epilepsy (87) alone cases. Altered proteins in Dual vs. AD included those associated with mTOR signalling related pathways, regulation of eIF4 and p70S6K (p = 1.62 × 10‐4) and mTOR signalling (p = 2.19 × 10‐2).

Conclusion

Our results provide insights into common mechanisms in epilepsy and AD and highlight the potential role of tau and mTOR signalling in both disease groups.
The Role of diet x gene interaction in LOAD2.Plcg2M28L mice
Authors: Rangel‐Barajas Claudia , Oblak Adrian L , Ingraham Cynthia M , Lloyd Christopher D , Territo Paul R , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T.
Published: January 2025

Background

Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome‐wide association studies (GWAS) originally identified Phospholipase C gamma 2 (PLCγ2) as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human‐based studies have corroborated and extended this association, promoting Plcg2 as one of the most important risk genes of both early‐onset and late‐onset AD, harboring both common and rare risk variants with relatively large effect on AD risk.

Method

To investigate the impact of Plcg2 gene expression on microglia biology and disease pathology, we have generated Plcg2M28L mice on an APOE4.Trem2R47H.hAb (LOAD2) background. Cohorts of mice were established at IU and aged to 18 months on a high fat diet (HFD). Animals began the HFD at 2 months of age and were longitudinally followed to 18 months of age. At 4, 12 and 18 months, mice received an MRI and blood draws for biomarker analysis. A second cohort of animals was analyzed cross sectionally at 4, 12, 18 and 24 months of age. PET studies were completed in a third cohort. Post‐mortem studies at both sites included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.

Result

Utilizing our multi‐analyte approach, we are able to correlate changes in the mice and human LOAD. Overall, at 18 months there is an increase in microgliosis in male mice that is age dependent. On a high fat diet, microgliosis is observed in both male and female within the cortex, but in the subiculum, IBA1 increased only in females.

Conclusion

Our findings provide evidence that Plcg2 plays an important role in LOAD and the addition of Plcg2M28L to a sensitized LOAD model (LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.
Lipid Droplet Dynamics are Modulated by Age and APOE Genotype
Authors: Stephens Isaiah O , Satish Diksha , Friday Cassi , Smith Katy , Devanney Nicholas A , Cornea Ana Maria L/K , Gordon Scott , Johnson Lance A
Published: January 2025

Background

Aging microglia accumulate lipid droplets (LDs), secrete pro‐inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (LOAD) and is associated with increased neuroinflammation and LD accumulation. Here, we aimed to determine if the effects of aging and the E4 allele are synergistic in causing the accumulation of LDs seen in LOAD. Specifically, we hypothesize that APOE genotype modulates the LD proteome and lipidome at baseline and with inflammation. Additionally, we show the effects of APOE genotype and age on LD accumulation in monocyte‐derived human macrophages treated with sex‐matched exogenous serum.

Method

Primary microglia were isolated from mice expressing human ApoE3 and ApoE4. Microglia were exposed to oleic acid (OA), LPS, OA+LPS, dead N2A cells, or dead N2As+LPS to stimulate an inflammatory response, then lipid droplet content was analyzed. To examine the impact of inflammation on LDs in vivo, ApoE3 and ApoE4 mice were injected with saline or LPS and liver tissue collected at 24h. Density gradient centrifugation was used for isolation of LD‐enriched fractions and these were analyzed using mass spectrometry proteomics. To determine the impact of age on circulating factors that may affect LD dynamics, human Peripheral Blood Mononuclear Cells (PBMCs) were treated with serum from different aged donors and the impact on LDs was analyzed.

Result

Primary microglia from ApoE4 mice accumulated significantly more LDs at baseline, with OA, LPS, and N2As as a percentage of E3 control. Proteomics revealed that LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for lipid b‐oxidation proteins. Lipidomics showed an increase in phosphatidylcholine distribution in the LD membrane of E4‐control and LPS‐treated droplets. Finally, a significant positive correlation between the age of serum samples used to treat human macrophages and LD accumulation in the PBMCs was observed.

Conclusion

In agreement with prior studies, E4 microglia accumulate more LDs compared to E3 microglia under all conditions tested. The proteomic profile of E4 LDs support the hypothesis that E4 expression increases inflammation under basal and stimulated conditions, causing a more robust response.
Investigating the additive effects of Alzheimer’s disease biomarker staging and subjective cognitive decline in the prediction of clinical progression
Authors: Stark Melina , Wagner Michael , Kuhn Elizabeth , Bürger Katharina , Düzel Emrah , Hellmann‐Regen Julian , Heneka Michael T. , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schmid Matthias , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Kleineidam Luca
Published: January 2025

Background

The identification of cognitively unimpaired individuals at risk of short‐term cognitive decline is a critical task for Alzheimer´s disease (AD) research. Cognitively normal individuals with amyloid and/or tau pathology have a high risk for short‐term cognitive decline. However, not all of these individuals show clinical progression. Individuals in clinical stage 2 of AD, characterized e.g. by subjective cognitive decline (SCD), are thought to be temporally closer to clinical progression to mild cognitive impairment (MCI), but this hypothesis has not been rigorously investigated yet.

Method

We included 195 memory clinic SCD patients and 83 cognitively normal participants without SCD (CN) with baseline CSF and longitudinal cognitive data from the observational DELCODE study. Participants were categorized into three AD biomarker stages (A‐T‐, A+T‐, A+T+) based on their baseline CSF Aβ42/40 and p‐tau181 status. The groups were compared in their longitudinal preclinical Alzheimer´s cognitive composite (PACC5) trajectories and average time until progression to MCI. Group differences in the time until progression to MCI, over eight years of follow‐up, were estimated with restricted mean survival time models. All analyses were adjusted for demographic covariates.

Result

Compared to the A‐T‐ group (62 CN, 123 SCD), A+T‐ (16 CN, 49 SCD) and A+T+ (5 CN, 23 SCD) participants showed significantly accelerated PACC5 decline and a faster progression to MCI (A+T‐: 2.7 [‐5.7‐11.2] and A+T+: 22.4 [8.1‐36.8] months earlier than A‐T‐;). SCD patients had a significantly faster PACC5 decline and progression to MCI (15.5 [9.8‐21.1] months) than CN participants. The effects of SCD and the biomarker stages on both outcome measures remained significant when the predictors were entered in the same models. In exploratory analyses, SCD patients tended to show a faster progression to MCI than CN participants within the same biomarker group (A+T‐: 19.0 [6.3‐31.7] and A+T+: 14.0 [‐20.8‐48.8] months earlier than CN in same biomarker group).

Conclusion

SCD provides incremental information for the identification of individuals at high risk of imminent cognitive decline beyond a biomarker‐based classification of AD pathology. In cognitively unimpaired individuals, the clinical stage should be taken into account additionally to AD biomarkers for an improved prediction of the time until clinical progression.
Molecular and functional analysis using Presenilin‐1 G206A mutation iPSC lines to understand age‐of‐onset variability in autosomal dominant Alzheimer disease
Authors: Celis Katrina
Published: January 2025

Background

Pathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of early‐onset Alzheimer disease (AD). Despite the high penetrance, substantial interindividual variability in age‐of‐onset (AOO) is observed among different PSEN1 mutations. Attempting to understand the molecular mechanisms leading to variability in AOO in PSEN1 mutations, we focused on three mutations located at codon 206 (G206A, G206S and G206D) of this gene. The G206A variant is associated with a wide range AOO, 30‐90 years, while G206S and G206D have a less variable AOO reported in only a few cases (30‐35 years). Molecular and functional analysis from induced pluripotent stem cells (iPSC) carrying these mutations may help us identify the transcriptomic changes and cellular pathways associated with AAO variability.

Method

We identified 46 carriers of the G206A mutation using whole genome sequencing from 182 families recruited as part of the Puerto Rican Alzheimer Disease Initiative (PRADI). We collected peripheral blood mononuclear cells (PBMCs) for iPSC generation from 19 of those 46 PRADI G206A carriers. We selected six G206A carriers, three with AOO <60 and three with AOO >65 years. CRISPR/Cas9 genome editing technologies were used to introduce the G206S, G206D and G206WT (wild type) variants from a G206A iPSC line. All eight lines (six G206A, one G206S and one G206D) will go under neuronal differentiation and spheroid generation protocol for transcriptomic, proteomic and AD‐related functional analysis.

Result

We have successfully reprogrammed six iPSC lines carrying the G206A mutation. CRISPR genome editing has been performed for the G206D and G206S variants. and confirmed by Sanger sequence. Next steps include neuronal differentiation and spheroids generation from iPSC lines, followed by bulk RNA sequencing from neurons, single cell RNA sequencing from spheroids and AD functional analysis including assays for Aβ40, Aβ42, APP, Tau, and NOTCH.

Conclusion

Our iPSC lines will be instrumental to identify potential molecular determinants of AOO in PSEN1 mutation carriers. Transcriptomic and functional data is in process and will be presented at the conference. These data will be informative for the identification of molecular changes associated with PSEN1 mutations in neurons and other cell types that will further increase our understanding of PSEN1 role in AD pathogenesis.
Feasibility of Using Smartphone‐Based Cognitive Testing Among People Living with Alzheimer’s Disease and Related Dementias
Authors: Moore Raeanne C , Kuehn Kevin , Khullar Diviya , Jantz Carissa , Song Jessie M , Padmanabham Prasanna , Mausbach Brent , Martin Jennifer L , Song Yeonsu
Published: January 2025

Background

Unsupervised high‐frequency cognitive‐ecological momentary assessment (EMA) on smartphones is increasingly used to assess preclinical risk for Alzheimer’s disease and related dementias (ADRD). While these tests are reliable and valid for individuals with preclinical ADRD, it is unclear whether administering cognitive EMAs to people living with ADRD is feasible and valid. Our study explored the feasibility and validity on cognitive EMA tests in people living with moderate to severe ADRD.

Method

A total of 31 with ADRD received cognitive EMA web links through their care partners' smartphone three times/day for seven days at baseline as part of an ongoing clinical trial of a dyadic sleep intervention. Of which, 23 completed any of three cognitive EMA tests using the NeuroUX platform (Quick Tap 1 [QT1], Quick Tap 2 [QT2], Matching Pair [MP]). We examined baseline adherence to cognitive EMA prompts, performance distributions, and within‐day variability of cognitive performance. We also compared this data to a normative sample.

Result

On average, participants completed 60% of cognitive EMAs (SD = 27%). This was lower than a normative sample of cognitively normal adults aged 20‐79 (N = 394; mean adherence = 88%, SD = 21%). Participants tapped the response correctly 78.68% (SD = 0.25%) of the time on QT1, a measure of psychomotor speed, and took an average of 936.83 milliseconds (SD = 294.86) to respond correctly (see Table 1 for comparison to normative data). On a measure of response inhibition (QT2), participants responded correctly on 33.07% of the items (SD = 0.19%), with mean correct response times of 602.19 milliseconds (SD = 238.18). Finally, participants scored a mean of 108.08 (SD = 65.60) on MP, a measure of processing speed. Performance on QT2 and MP (% of correct response) did not differ throughout the day; however, participants response times to QT2 was significantly slower in the morning than in the afternoon or evening (morning M = 643.81; afternoon M = 587.14; evening M = 578.19; F(df = 1) = 7.24, p < 0.01).

Conclusion

Current findings extend research on people with preclinical ADRD, demonstrating that reliable and valid cognitive EMA data can be obtained from this group and employed in research.
Production and characterization of human tau protein with site‐specific phosphorylation utilizing E. coli with an expanded genetic code
Authors: Ammermann Erik J , Cho Yongku P
Published: January 2025

Background

With insight into the elevated levels of phosphorylation of diseased tau, it is believed that specific modifications occur in a time‐dependent manner that contribute to tau’s role in Alzheimer’s disease pathogenesis and progression. Present methods to obtain phospho‐tau (p‐tau) from post‐mortem tissue or recombinantly are insufficient to answer the foremost questions in the field, and there is currently no way to study each disease‐relevant modification reproducibly or in isolation. To this point, learning about tau phosphorylation at the resolution of a single modification has been a major obstacle in clarifying whether certain sites are causative of disease or just a by‐product of other harmful mechanisms. Furthermore, a standardized p‐tau reagent with known, consistent modifications is urgently needed to develop diagnostic and phospho‐specific tools.

Method

Using a phosphoserine orthogonal translation system, we describe a method to produce full‐length human tau in engineered E. coli with genetically defined phosphoserine (pSer) sites. This p‐tau can be readily purified with traditional chromatography techniques and subsequently used for in vitro assays to assess differences in tau biochemistry due to individual PTMs for the first time. To date, we have produced 12 different p‐tau variants with a single disease‐relevant pSer site ranging from pSer199 to pSer422.

Result

In experiments to measure tau aggregation in vitro (thioflavin‐T and HEK cell biosensor), our preliminary results indicate that the disease‐associated pSer396 modification of 2N4R tau may have increased aggregation and seeding capabilities relative to other tested pSer tau. Strikingly, in the thioflavin‐T experiment, spontaneous aggregation of pSer396 was observed in which no heparin was added to the reaction mixture. Also, using Western blot, we clearly demonstrate a simple but powerful method to assess the specificity of phospho‐specific antibodies.

Conclusion

The ability to readily produce recombinant human tau with known PTMs will be a critical tool in helping researchers develop, validate, and assess the specificity of p‐tau detection platforms and antibody‐based technologies. With the idea of developmentally significant PTM sites in mind, we have preliminary results suggesting that even single tau PTMs can dramatically alter tau biochemistry and lead to disease‐like molecular behaviors.