bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence and Severity of Lewy Body Pathology is Modulated by Sex and ApoE4 Zygosity in a Neuropathologically‐Confirmed Alzheimer’s Disease Cohort
Authors: Valcic Mila , Khoury Marc A , Fornazzari Luis R , Churchill Nathan W , Schweizer Tom A. , Fischer Corinne E. , Munoz David G.
Published: January 2025

Background

The APOE ε4 allele (ApoE4) is a known genetic risk factor for developing Alzheimer’s disease (AD). Previous work by our group demonstrated that female ApoE4 homozygotes with Lewy body (LB) pathology were significantly more likely to experience psychosis compared to female ApoE4 non‐carriers, whereas there was no dose‐dependent difference found in males (Valcic et al., 2022). The objective of this study was to examine LB pathology presence and severity in males and females across ApoE4 status, with a particular interest in female ApoE4 homozygotes.

Method

Demographics, APOE genotype, and LB pathology data was collected in individuals with neuropathologically‐confirmed AD (n=1,234) from the National Alzheimer’s Coordinating Center (NACC). Bayesian Multilevel Regression was used to predict the probability of LB pathology presence in males and females across ApoE4 status (0, 1, 2 ε4 alleles). An Ordinal Regression was used to examine the relationship between LB pathology severity (brainstem‐predominant (mild), limbic or amygdala‐predominant (moderate), neocortical‐predominant (severe)) and ApoE4 status, stratifying by sex.

Result

While males had a higher probability of exhibiting LB pathology compared to females, after stratifying by ApoE4 status, female ApoE4 homozygotes showed the highest probability of LB pathology at a 91.1% Highest Density Interval (91.1%HDI[0.12: 0.95]) across both sexes. Within females, ApoE4 homozygotes showed a significantly higher probability of having moderate to severe LB pathology relative to other groups (p =.02). Within males, there was no significant relationship between ApoE4 status and LB pathology severity.

Conclusion

This study revealed that sex and zygosity modulate the effect of ApoE4 on presence of LB pathology and LB severity in neuropathologically‐confirmed AD patients. Specifically, female ApoE4 homozygotes had the highest probability of having LB pathology, as well as greater LB pathology severity. Future work should explore the association between LB pathology severity and psychosis while stratifying for sex and ApoE4 status.

Reference: Valcic, M., Khoury, M. A., Kim, J., Fornazzari, L., Churchill, N. W., Ismail, Z., De Luca, V., Tsuang, D., Schweizer, T.A., Munoz, D.G, & Fischer, C. E. (2022). Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically‐Confirmed Alzheimer’s Disease Cohort. Brain Sciences, 12(9), 1266.
Epidemiological and genomic analyses identify drug classes associated with Lewy body dementia
Authors: Scholz Sonja W
Published: January 2025

Background

Lewy body dementia (LBD) is the second most common neurodegenerative dementia after Alzheimer’s disease which remains poorly understood. Disease‐modifying therapies for LBD are critically needed. We performed a population‐based case‐control study of U.S. Medicare participants with LBD and matched controls to identify drugs that are significantly associated with disease risk.

Method

A total of 148,170 U.S. Medicare and 1,253,043 controls were included in the study. We estimated the association of LBD risk with 1,017 prescription drugs. We then applied genetic correlation analyses to genomic data generated for LBD and cardiovascular traits to investigate causal effects.

Results

Using broadly adjusted logistic regression models, we discovered significantly reduced LBD risk associated with drugs used to treat cardiovascular diseases (antihypertensives: odds ratio = 0.72, 95% confidence interval = 0.70–0.74, p‐value = 0; cholesterol‐lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83–0.87, p‐value = 0; and antidiabetics medications: odd ratio = 0.83, 95% confidence interval = 0.62–0.72, p‐value = 0). Notably, antidiabetic medications were associated with a larger risk reduction among Black LBD patients than other racial groups. Genetic correlation analyses identified shared genetic risk between LBD and low‐density lipoprotein cholesterol levels, hypertension, and type 2 diabetes mellitus.

Conclusions

Our data suggest that the genetic architecture of LBD and cardiovascular traits overlap and that assiduous management of cardiovascular risk factors may be beneficial in this this patient population.

Reference: Scholz SW et al., Brain Commun. 2023 Dec 18;6(1):fcad346.
Associations between serum metabolic syndrome indicators levels and cerebrospinal fluid pathological protein
Authors: Ding Jiayi , Quan Meina , Jia Jianping
Published: January 2025

Background

Metabolic syndrome (MetS) was associated with an increased incidence of mild cognitive impairment (MCI) and progression to dementia. However, little is known about why this occurs. This study was to examine the correlation between the MetS indicators and cerebrospinal fluid (CSF) pathological protein biomarkers to investigate this mechanism.

Methods

70 normal cognition (NC), 79 MCI, and 150 dementia participants were included, with the results of lumbar puncture and peripheral blood biochemistry. The CSF levels of amyloid (Aβ) 42, total tau (T‐Tau), phosphorylated tau (P‐Tau) and Aβ42/40 ratio were selected as the biomarkers of pathological protein. The body mass index (BMI) and the plasma high density lipoprotein cholesterol (HDL‐C), uric acid (UA), low density lipoprotein cholesterol (LDL‐C), triglyceride (TG) and homocysteine levels were selected as markers of MetS. Linear regression model was used to analyze the correlation, controlling for age, sex and apolipoprotein E genotype.

Results

In all participants, BMI and TG were negatively correlated and LDL‐C was positively correlated with CSF Aβ42/40 ratio. (Figure 1) UA and TG were negatively correlated with CSF T‐tau levels.(Figure 2) BMI, UA and TG were negatively correlated and HDL‐C was positively correlated with CSF P‐Tau concentrations. (Figure 3) In the NC group, no correlation was observed. In the MCI group, LDL‐C was negatively correlated with Aβ42/40. Higher levels of UA and TG were correlated with lower CSF T‐Tau concentrations. BMI and TG levels were negatively correlated and HDL‐C was positively correlated with CSF P‐Tau levels. In the dementia group, BMI was positively associated and LDL‐C was negatively associated with CSF Aβ42/40 ratio. HDL was negatively correlated with and homocysteine was positively correlated with CSF Aβ42 levels. UA and TG were negatively correlated with CSF T‐Tau levels. TG and homocysteine levels were negatively correlated and HDL‐C was positively correlated with CSF P‐Tau levels.

Conclusion

The pathological proteins concentrations in the CSF of the elderly were differentially associated with MetS indicators in different stages of dementia. These findings suggest that serum lipids modulate CSF pathological proteins, which could offer new approaches to slowing disease progress and reducing the incidence of dementia.
Impact of Site Size on Data Quality in Early Alzheimer’s Disease Clinical Trials
Authors: Kott Alan , Wang Xingmei , Reksoprodjo Petra , Iacob Andrei , Miller David S.
Published: January 2025

Background

Clinical trial sponsors rely on research sites to identify and enroll appropriate study participants and to correctly and reliably assess symptom severity and function over the course of the trial. Low‐recruiting sites represent a large financial and operational burden and may negatively impact trial success either by selecting inappropriate participants and/or high prevalence of data quality issues. We previously reported that >60% of sites in schizophrenia clinical trials recruited ≤5 participants. Here we analyze 3 large dementia trials to assess the proportion of low‐recruiting sites and compare their data quality with the remaining sites.

Method

Data were obtained from 3 large early dementia clinical trials totaling 834 sites. Sites were divided into two groups based on the number of randomized subjects: 1. sites with more than 5 randomized subjects (high‐recruiting sites) and 2. sites with 5 or less randomized subjects (low‐recruiting sites). Data quality issues were defined as administration and scoring errors on relevant scales. These errors were summed per site and then compared by site size using Poisson regression with the site size, study and their interaction as predictors and the number of possible hits as exposure.

Result

71 (8.5%) sites did not randomize a subject, 43 (5.2%) sites randomized one subject, and 377 (45.2%) sites randomized ≤5 subjects. Overall, administration and scoring errors were more frequent at low‐recruiting sites (seen at 41.9% visits) compared to 35.3% at the high‐recruiting sites. 2 studies show significantly higher IRRs, 1.59 (1.46, 1.74) and 1.2 (1.15, 1.25) respectively, while the third study has an IRR close to 1 but not statistically significant.

Conclusion

Our results indicate that low‐recruiting sites (arbitrarily defined as randomizing ≤5 participants) are frequent in large dementia trials. These sites pose considerable cost to sponsors, but more importantly, are more likely to provide questionable data quality. While a single site like this only represents a small risk, in aggregate, they can pose a serious challenge. Clinical trial sponsors should therefore consider strategies to minimize the impact of low‐recruiting sites on study outcomes.
Validation of the Italian consensus recommendations for the biomarker‐based etiological diagnosis of mild cognitive impairment: study design and preliminary data
Authors: Solorzano Claudio Singh , Festari Cristina , Orini Stefania , Castagna Eleonora , Ramusino Matteo Cotta , D'Antonio Fabrizia , Crosta Adolfo Di , Masòtino Alessia , MASSA FEDERICO , Mazzonetto Alice , Panigutti Massimiliano , Ravì Noemi , Pievani Michela , Bonanni Laura , Bruno Giuseppe , Cagnin Annachiara , Gatta Roberto , Frisoni Giovanni B.
Published: January 2025

Background

In 2020, five Italian scientific societies issued diagnostic recommendations to improve the rational and combined use of biomarkers in the clinical practice of Italian memory clinics (Boccardi et al., 2020). The present project will aim to compare the most frequent diagnostic workups in three academic memory clinics before (pre‐recommendations: January 2018 ‐ December 2019) and after (post‐recommendations: October 2022 ‐ October 2023) the release of the recommendations to assess their implementation in clinical routine. Preliminary results on pre‐recommendations data are presented here.

Method

We retrospectively reviewed the medical charts of consecutive patients referred to the academic memory clinics of Padova, Chieti, and Roma for a first visit in the pre‐recommendations period. The collected information included socio‐demographic data, number and dates of clinical visits and biomarker exams (i.e., FDG‐, amyloid‐, tau‐PET, cerebrospinal fluid [CSF], DAT SPECT/PET, and cardiac MIBG scintigraphy). A diagnostic hypothesis was extracted for each clinical visit until the final diagnosis.

Result

Since October 2022, 500 patients’ medical charts were reviewed. Patients were divided into three groups: 148 (30%) patients came to clinical observation not for diagnostic purposes (e.g., second opinion, disability claim), 242 (48%) received a diagnosis based on neuropsychological assessment and morphological imaging only, and 110 (22%) were in a biomarker‐based diagnostic pathway. The latter group included 31 patients with Alzheimer’s disease (AD), 19 with frontotemporal lobar degeneration (FTLD), 28 with a Lewy body spectrum disease (LBD), and 32 with non‐neurodegenerative aetiology or vascular dementia. Biomarker‐based diagnoses of AD, FTLD and non‐neurodegenerative diseases were commonly based on FDG‐PET (AD: 77%, FTLD: 84%, non‐neurodegenerative: 66%) and CSF (52%, 37%, and 44%). In LBD (n = 28), the first‐choice biomarker was FDG‐PET (61%), followed by DAT SPECT/PET (39%).

Conclusion

This preliminary analysis outlines the most frequent diagnostic pathways, providing the prevalence of the use of biomarkers in Italian academic memory clinics in the pre‐recommendations period. Once the post‐recommendations data collection is completed, we will evaluate whether the recommendations are feasible and usable in real‐world clinical workups by applying process‐mining techniques (Gatta et al., 2020) to estimate the prevalence and type of deviations from the ideal pathway based on recommendations.
Systematic review of digital self‐management interventions in dementia care: Exploring the impact of wearable technology, smart homes, and mobile applications on patient outcomes
Authors: Cornelius Gary
Published: January 2025

Background

The increasing significance of self‐management in dementia care arises from earlier diagnosis, improved understanding of patient‐modifiable factors, and advancements in treatments. The growing acceptance of patient care planning, especially self‐management, is further supported by health professionals and public health initiatives aimed at extending healthspan.

Method

This systematic review evaluates the efficacy of self‐management tools in enhancing the quality of life for adults with dementia and mitigating undesirable behaviours associated with the condition. A comprehensive search spanning ten years across nine databases was conducted, leading to the screening of over eight hundred articles. A highly relevant collection of studies, focusing on adults with dementia’s interaction with digital technologies, was selected. These studies were analysed using the Mixed Methods Appraisal Tool (MMAT) and a custom‐designed characterization table to address specific research questions.

Result

The review highlights that self‐management approaches such as aiding functional independence, wellbeing support, engagement, monitoring, and detecting abnormal behaviour are effective. The studies utilized various assessment methods including multimodal sensing, caregiver feedback, and machine‐based prompting. Effective use of smart home sensors, health watches, wearable technologies, cameras, Internet of Things (IoT) networks, robots, and other devices was also noted.

Conclusion

Technologies for self‐management notably enhance patient well‐being, with effective strategies including monitoring for abnormalities, socially assistive robots, machine prompting, sensory interventions, and cognitive support. Future research could improve by aligning interventions with individualized activities that promote well‐being, employing standardized outcome measures, and controlling for external factors such as known patient disease‐modifying factors.
Family carers experiences of compassion for self, other and receiving compassion
Authors: Kupeli Nuriye , Cooper Claudia , Bruun Andrea , Dillon Laura , Reilly Pepsi , White Nicola , Sampson Elizabeth L
Published: January 2025

Background

Family carers of people living with dementia provide care over many months or years with little to no formal support. Carers’ experiences of compassion for themselves and others including receiving compassion can influence their caregiving experience and the quality of care they provide. However, little is known about healthcare professionals (HCPs) understanding of how compassion is experienced by family carers and how best HCPs can support family carers to cultivate and maintain compassion for themselves and others.

Methods

This study used qualitative interviews to explore family carers experience of compassion for themselves and others (including receiving compassion from others) while caring for someone living with dementia. Inductive thematic analysis was used to explore and report the barriers and facilitators to family carers experiences of compassion.

Results

Interviews with ten family carers (nine current and one former carer) comprising of five daughters, three wives, one husband and one son were undertaken. Barriers and facilitators were identified for compassion for self, others and receiving compassion. While facilitators to compassion included having the opportunity to maintain an identify outside of caring role, positive memories, and shared understanding, experiences that made it difficult for carers to maintain compassion included the perception that one needs to sacrifice own needs and feelings of guilt and shame.

Conclusions

Preliminary findings indicate that whilst carers of people living with dementia acknowledge that compassion is important, they indicate that the caring role could be a barrier to experiencing and maintaining compassion. Future research needs to focus on developing supportive interventions designed to addressing factors that may hinders carers abilities to cultivate and maintain compassion.
Reducing psychotropic medication use in patients with dementia: the impact of multimodal care‐communication skill training for medical staff in long term care hospital
Authors: Honda Miwako , Kobayashi Masaki
Published: January 2025

Background

Psychotropic drug prescriptions are commonly used to manage behavioral and psychological symptoms of dementia in elderly patients in long‐term care facilities. The prevalence of psychotropic drug use in this population raises concerns due to potential side effects, polypharmacy and quality of life of the patients.

Aim

To assess the trends in psychotropic drug prescriptions for elderly patients with dementia following the continuous implementation of multimodal comprehensive care communication skills training for staff in a long‐term care hospital.

Method

This retrospective single‐centre cross‐sectional study utilized the database of an urban public long‐term care hospital, from 2016 to 2020. The study involved 130 hospital staff, comprising 52 nurses, 48 professional caregivers, 7 rehabilitation staff, 3 physicians, and 3 pharmacists. All staff members underwent a French origin multimodal comprehensive care communication skill training (Humanitude) from October 2014 to December 2015, followed by continuous monthly training sessions until the conclusion of the study in 2020. Antipsychotics prescription rates for patients aged over 65 years with dementia were measured throughout the study period. No significant changes in the proportion nor severity of patients' disease backgrounds were observed during the study period.

Results

A total of 506 eligible patients were identified, with a mean age of 86.0 years (IQR 81.0‐90.0), and 283 (55.9%) were women. The prescription rates for psychotropic drugs among residents with dementia showed a significant decrease (43.5% in 2016, 27.0% in 2020, p = 0.01). Notably, the prescription rates for anxiolytics demonstrated a significant reduction (from 4.7% to 0.0%), while rates for antipsychotic drugs, hypnotics, antidepressants, antiepileptic drugs, and lithium remained unchanged over time. The prescription rates for antidementia drugs significantly decreased from 15.3% to 4.0%.

Conclusion

The study found a significant reduction in the prescription rates of psychotropic drugs after implementing multimodal comprehensive care communication skills training for staff at a long‐term care hospital. This outcome indicates that providing skill training to hospital staff is associated with a decrease in behavioral and psychological symptoms of dementia among patients, resulting in a reduced need for psychotropic drugs. The enhanced communication skills among long‐term care staff demonstrate a tangible impact on reducing drug use among patients with dementia.
Phospolipase D Insights: Elevated Levels in Mild Cognitive Impairment, Therapeutic Reduction in Alzheimer's Patients
Authors: Pereira Cícero Augusto Costa , Talib Leda Leme , Forlenza Orestes Vicente , Gattaz Wagner Farid
Published: January 2025

Background

Membrane lipid compromise is also related to AD pathology, a large family of enzymes such as phospholipases that act on membrane integrity, cell signaling, and cellular processes is impaired during the disease phase. Membrane integrity is affected by the B amyloid by the pathological process of AD, moreover, releasing neurotoxic enzymes and vesicles consequently losing important neurotransmitters. Dysregulation of phospholipase D (PLD) can disrupt the plasma membrane and potentially contribute to worsening AD pathology.

Method

The study was conducted at the Institute of Psychiatry, University of Sao Paulo Medical School, Brazil. The plasma samples consisted of Mild Cognitive Impairment (MCI) (n = 20), AD patients (n = 18), and healthy controls (HC) (n = 19). Subjects with other psychiatric or neurological disorders were excluded. PLD activity was measured by a fluorescence method in duplicate by the Amplex® Red Phospholipase D Assay Kit (Thermo Fisher Scientific).

Result

PLD activity showed an increase significantly in the MCL group compared to other groups (p=0.030).

Conclusion

The early stages of dementia have high PLD activity. Our results suggest increased PLD activity significantly in MCL individuals compared to other groups. The highlight its AD with treatment has a decrease in PLD activity compared to other groups.
Utility of the PROMIS Physical Function measure using differential item functioning among individuals with cognitive impairment
Authors: Lovett Rebecca , Russell Andrea , Vogeley Abigail , Bonham Morgan , Graham Eileen , Mroczek Daniel , Yoshino‐Benavente Julia , O'Conor Rachel , Opsasnick Lauren , Batio Stephanie , Wolf Michael S
Published: January 2025

Background

Impaired functional status is a central diagnostic feature of Alzheimer’s disease and related dementias (ADRD). Informant reporting is often relied upon, given concerns surrounding the ability of persons with ADRD to validly self‐report symptoms. We sought to investigate how cognitive impairment severity impacts psychometric properties of the Patient‐Reported Outcomes Measurement Information System Physical Function (PROMIS‐PF) scale.

Methods

Data from 396 older adults participating in a longitudinal cohort study on aging was used for this analysis. Cognitive function was assessed using an extensive neuropsychological battery consisting of 13 tests across 5 cognitive domains; z‐scores were calculated for each test and used to determine cognitive impairment severity. Physical function was measured using the PROMIS‐PF short‐form 10a. Differential item functioning (DIF) analyses were conducted using the lordif package in R with Monte Carlo simulations.

Results

Participants were on average 71.2 years old (SD 5.3), primarily female (72.0%), white (54.3%), and well‐educated (60.0% at least some college). Nearly two‐thirds were cognitively normal (72.5%), while 14.4% and 13.4% had a mild and moderate/severe cognitive impairment, respectively. Seven out of 10 PROMIS‐SF items were flagged for DIF. Direction of DIF varied; participants with mild impairment exhibited a tendency to underestimate their physical function, while those with moderate/severe impairment were characterized by a tendency to overestimate. McFaddens pseudo R2 effect sizes were all below published thresholds of 0.13 (range: 0.01‐0.05). Test characteristic curves (TCC) were overlapping between the 3 groups.

Conclusions

Findings indicate the presence of DIF by cognitive impairment severity on the PROMIS‐PF measure, although the magnitude of effect and overlapping TCC curves suggest the observed DIF was negligible. Nevertheless, researchers and clinicians should be aware that individuals with a cognitive impairment may respond differently to certain items on this measure and further study is needed to evaluate measurement bias among patients with cognitive impairment, including ADRD. However, overall, our evidence suggests patients with varying levels of cognitive impairment can provide reliable estimates of physical function using this measure. This has implications for researchers and clinicians seeking to assess functional status among older adults with ADRD, particularly if supplemental reports of functional status are not feasible or unavailable.
Immigration Status and Cognitive Function among Older Adults
Authors: Cheng Yan , Lakdawala Adnan , Ahmed Ali , Zamrini Edward , Zeng Qing
Published: January 2025

Background

Prior research on immigration and cognitive functioning was limited with conflicting findings. This study seeks to understand the association between immigration status and cognitive function in a representative sample of the US population and examine physical activity and nutritional intake’s interaction with immigration status.

Method

The study cohort included 2,898 participants (673 immigrants and 2225 non‐immigrants) from US National Health and Nutrition Examination Survey (NHANES) 2011‐2014 who underwent at least one cognitive function test. Demographics, vital signs, cardiovascular diseases, physical activity, and nutrition were compared between immigrants and non‐immigrants by mean or proportion. Standardized z‐scores were calculated for each nutrient to ensure comparability. Cognitive function was assessed through four test scores (animal fluency, digit symbol, Consortium to Establish a Registry for Alzheimer’s Disease [CERAD], and global score). To account for potential cognitive disparities, standardized z‐scores were calculated for cognitive function scores within age, education, and language strata. Scores in the lowest quartile were classified as low. Multivariate logistic regressions were conducted to estimate the association between immigration status and risk of low standardized cognitive function scores, adjusting for all covariates. NHANES survey weights were applied to ensure the results are representative of US civilians.

Result

Compared to the non‐immigrants, the immigrants in our sample were younger and less educated. (Table 1). Our analysis found that being an immigrant was significantly associated with a low global cognitive function score (OR = 2.13, 95% CI = (1.34, 3.40), p = 0.0024) (Table 2). Higher protein, folate and theobromine intakes were associated with a higher global cognitive function score, while higher carbohydrate and zinc intakes were associated with a lower score. No interaction was found between nutrient intakes and immigration status. Increased physical activity was associated with the reduced risk of low animal fluency score, especially beneficial in non‐immigrants (Figure 1).

Conclusion

Being an immigrant was associated with low cognitive function after controlling age, education, language, and other covariates. A higher intake of protein, folate, and theobromine were found to be protective, though they did not have significant interactions with immigrant status.
Exploring digital cognitive measures as non‐invasive biomarkers: Association with AD plasma biomarkers
Authors: Ding Huitong , Karjadi Cody , Devine Sherral A. , Gurnani Ashita S. , Sunderaraman Preeti , Mez Jesse , Farrer Lindsay A. , Au Rhoda , Lin Honghuang
Published: January 2025

Background

Plasma amyloid and tau levels are known to be associated with the risk of Alzheimer’s disease (AD). In recent years, digital cognitive assessment has been increasingly recognized as a potential tool for long‐term cognitive monitoring. This study aims to explore the potential of digital cognitive metrics as efficient and low‐cost alternatives to plasma biomarkers.

Method

This study included participants from the Framingham Heart Study who had either their spoken responses to neuropsychological examinations digitally recorded or had completed the digital Clock Test (dCDT), along with plasma biomarker measurements taken within five years. Simoa™ Tau 2.0 Kit and INNO‐BIA plasma Aβ were used for tau, and Aβ40 and Aβ42 measurement, respectively. The study analyzed digital cognitive metrics, comprising 65 acoustic features extracted via OpenSMILE software and 101 features derived from the dCDT. Linear regression models, adjusted for age and sex, were employed to examine the association between these digital cognitive metrics and plasma total tau, Aβ40, and Aβ42 levels.

Result

This study included 4274 participants (mean age 57±14 years old, 53.7% women). Table 1 shows the top digital cognitive metrics associated with plasma biomarkers. Notably, plasma total tau was associated with 38 acoustic features. The most significant association was observed between audspec_lengthL1norm (sum of the auditory spectrum) and plasma tau (beta=‐0.09, SE = 0.03, P<0.001). Among the dCDT features, COMTotInkLengthCC, which represents the total drawing length of pen strokes in the command clock drawing, showed the most significant association with the plasma total tau level (beta=‐0.13, SE = 0.06, P=0.023).

Conclusion

Our results demonstrate an association between acoustic and digital clock drawing with plasma total tau, which is consistent with previous research that finds that cognitive performance is linked to AD tau pathology. These results highlight the promise of these digital cognitive metrics as an easily scalable, low‐cost screening tool for those at high risk for AD. Future investigations to test the robustness of digital cognitive metrics as a surrogate screening measure will be critical in tackling AD pathology.
Deep‐learning‐based Polygenic Dementia Risk for Alzheimer’s Disease
Authors: Li Linke , Gurcan Metin Nafi , Luo Sheng , Ma Da
Published: January 2025

Background

Alzheimer’s Disease (AD) is a common form of dementia among the elderly with a large percentage of estimated heritability. Conventional polygenic risk analysis only accounts for the linearly combined genomic effects of single nucleotide polymorphisms (SNPs). On the other hand, a deep‐learning‐based approach is able to uncover nonlinearly associated effects from data with high‐dimensional features such as genomics. This study aims to derive deep‐learning‐based polygenic risk analysis for AD through deep‐learning‐based classification analysis.

Methods

793 patients’ genetic data were extracted from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) GO/2 cohorts genetic database, with sex, age, and dementia diagnosis data extracted from ADNI clinical data. After quality control, 760 patients remained in the study and their SNP data was then imputed. Genome‐wide association study (GWAS) was conducted to determine the chromosome for study. One‐dimensional convolutional neural networks (1D‐CNN) were trained to discern phenotype‐associated SNPs for developing disease classification models. Subjects were classified into either cognitively normal & mild cognitive impaired (N = 542), or diagnosed with AD (N = 212) during the study period. The categorical information of SNPs (0, 1, or 2 alleles) on chromosome 19, containing APOE genes, was used as the input features for 1D‐CNN‐based disease case classifier model, with a 75/25 train/test split to evaluate. The weighted cross‐entropy function was used for the imbalanced AD and non‐AD cases in the samples.

Results

GWAS results showed strongest AD association for chromosome 19, which was selected for CNN dementia classification model training, while potential associated SNPs were also revealed on chromosome 1 (Figure 1). The model achieved area‐under‐the‐curve (AUC‐ROC) of 0.60. The sensitivity and specificity are 39.06% and 77.78%, respectively, and the balanced accuracy is 58.42%. Figure 2 shows the corresponding confusion matrix.

Conclusion

The GWAS results reinforce the APOE region’s established association with AD. The 1D‐CNN’s model tended to misclassify diseased individuals, potentially due to the fact of including MCI patients with a potential risk of AD in the control group. Future work will include refining the model hyperparameter as well as collecting a more disease‐balanced dataset.
Subject‐level Detection of Focal Neurodegeneration Using Spatiotemporal Connectomics: Towards Atrophy Characterization in Preclinical Alzheimer’s Disease
Authors: Sánchez Cristina , Diez Ibai , Bueichekú Elisenda , Kim Chan‐Mi , Grothe Michel J. , Sanchez‐Juan Pascual , Sepulcre Jorge
Published: January 2025

Background

Brain atrophy is a normal part of healthy aging, but it is aggravated by several neurodegenerative diseases. Previous studies have described a large heterogeneity in individual neurodegeneration patterns, but the underlying brain mechanisms are currently not fully understood. From a graph theory‐based framework, the estimation of subject‐specific focal or multifocal brain atrophy in healthy aging and in the preclinical stage of different neurodegenerative diseases, such as Alzheimer's disease (AD), will help to better understand individual atrophy networks and likely improve prediction of phenotypic heterogeneity in disease trajectories. This study aimed to develop a novel spatiotemporal connectomic method based on graph theory applied to serial MRI measurements to identify neurodegeneration focality (i.e., unifocal or multifocal atrophy patterns) in healthy aging at the single‐subject level.

Method

The study included a unique sample of 79 older cognitively normal participants from the the Vallecas project who underwent longitudinal T1 MRI scanning with 8 follow‐up timepoints over 9,46±1,97 years. Voxel‐based morphometry was used to define the brain atrophy topology of each subject, and uni‐ or multifocal atrophy patterns were identified using a graph theory approach based on structural similarity between each voxel and the rest of the brain across serial gray matter measurements (Figure 1).

Result

We identified individualized atrophy phenotypes characterized by different graph morphologies (Figure 2), which could be classified into three main groups based on their connectivity behavior. One group of subjects was characterized by atrophic voxels with a coordinated behavior, another with a predominance towards divergent or discoordinated behavior, and a third group that laid between these two extremes.

Conclusion

We present a novel analytical tool for characterizing individualized atrophy phenotypes in healthy subjects based on graph theory and structural similarity analyses of longitudinal MRI data. This method may help to describe the first structural events in preclinical AD and other neurodegenerative diseases and, therefore, could be crucial for predicting differences in disease phenotype and progression in single subjects.
Caregiver Needs and Resources—2023 Summer Styles Survey, United States
Authors: Walker Jenny A , Kilmer Greta
Published: January 2025

Background

The United States population is aging, with more individuals requiring care—a shift that has made addressing the needs of the nation’s caregiver population a public health priority. Understanding the resources caregivers use and need can inform those public health efforts.

Method

We examined 2023 Summer Styles survey data addressing caregiver services and support among U.S. adult caregivers (n = 437). Participants responded to questions about their need for and utilization of seven resources: out‐of‐home services, in‐home services, support groups or classes, care recipient food and nutrition support services, care recipient transportation services, care recipient financial planning services, and caregiver training opportunities. We further analyzed results from caregivers reporting that it was somewhat or very difficult to afford household expenses (n = 90), and those who care for a person with dementia or another cognitive impairment (n = 96). All percentages were weighted to match the U.S. Current Population Survey proportions.

Result

Overall, 45.5% of the surveyed caregivers indicated that they have utilized or would utilize one or more resource type. In‐home services were the most common (33.1%), followed by transportation services (26.6%) and care recipient food and nutrition services (25.2%). Care recipient financial planning resources were the least common (13.0%). About one third (34.2%) of caregivers indicated they would use at least one of the seven resources, but that it was unavailable or not known to be available to them. Among caregivers who struggle with household expenses, transportation services were the most frequently identified (29.3%) resource they would use if available. Among those who care for a person with dementia or another cognitive impairment, in‐home services was the most frequently identified (21.8%) resource they would use if available.

Conclusion

These results suggest that caregiver resource use and need varies qualitatively based on financial limitations and the diagnosis of the care recipients. Additionally, over a third of caregiver respondents indicated that they would use a service or tool, but it is currently not available or known to be available to them. These results can help inform public health decision‐making in addressing the needs of the nation’s caregivers.
Does education years delay Alzheimer’s disease in cognitively normal oldest old?
Authors: Sohrabi Hamid R , Goozee Kathryn G , Weinborn Michael , Smith Stephanie Rainey , Taddei Kevin , Martins Ralph N
Published: January 2025

Background

Research on cognitive reserve (CR) in individuals aged 80 years old and above has resulted in inconsistent findings, mostly showing a relationship with baseline cognitive abilities but not follow up assessments. The effects of amyloid burden on the relationship between CR, cognitive decline and dementia in oldest old warrants further study in the presence of APOE e4. We hypothesised that CR in oldest old (≥80 yrs old) adults will result in different trajectories, depending on being amyloid PET positive or negative. Specifically, this study was to determine whether the relationship between CR and cognition is mediated by amyloid load in very old individuals.

Method

Data of 115 participants aged 80 years and above at baseline and one follow‐up was analysed for this study. Participants were recruited from the Western Australia Memory Study (WAMS, Perth) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) Study (Sydney, Australia). In both sites participants have undergone amyloid imaging, as well as a comprehensive neuropsychological assessment, APOE genotyping and AD‐related blood‐based biomarkers analysis.

Result

Preliminary results indicated a non‐significant relationship between education years, as the proxy for CR, and baseline cognition. Similar not‐significant findings was observed between CR and amyloid load. Individuals positive or negative for amyloid burden on the brain at baseline, as well as carriage of APOE e4 did not differ on years of education. Of interest, APOE e4 allele carriers were not different from not‐carriers on amyloid load in the brain. Due to nonsignificant relationships between the variables of interest, in both cross‐sectional as well as longitudinal data, further mediation analysis was not carried out.

Conclusion

Our nonsignificant results indicated that the commonly reported relationship between CR, cognitive function, amyloid load in older adults may not be present in individuals aged 80 years old and above. Although these findings are consistent with previous reports, other factors including longevity genetic factors that promote preserving cognition in oldest adults as well as lifestyle factors should be considered. Further analysis of such factors is currently ongoing and may result in interesting outcomes for this cohort.
Associations of Neighborhood Walkability with Cognitive Impairment Depend on Geographic Context
Authors: Rosso Andrea L , Shaaban C. Elizabeth , Cheng Greta , Buchanich Jeanine M , Butters Meryl A , Cohen Annie , Dubowitz Tamara , Faulkner Melanie Y , Gogniat Marissa A. , Lopez Oscar L. , Saeed Anum , Reis Steven E. , Troxel Wendy M , Weinstein Andrea M.
Published: January 2025

Background

Neighborhood walkability may affect cognitive impairment through promotion of physical activity. However, most studies are conducted in urban, predominantly White samples. We assessed how walkability is related to presence of cognitive impairment and whether the relation differs by neighborhood population density (differences in likelihood of promoting physical activity) and/or racial composition (differences in quality of neighborhood resources). We hypothesized that lower walkability is related to greater likelihood of having cognitive impairment and that this association is stronger in areas with higher population density (i.e., more urban) and with a lower percentage of Black residents.

Methods

We used cross‐sectional data from 4 harmonized studies of cognition and dementia across Southwestern Pennsylvania (n = 1625, Table). Walkability was defined by quartiles of the Environmental Protection Agency walkability index at the participant’s residential census tract. Cognitive impairment was defined as clinically adjudicated mild cognitive impairment or dementia (3 studies) or a Clinical Dementia Rating of ≥0.5 (1 study). US census data were used for population density (> or ≤ 2500 people/square mile) and racial composition (0%‐10%, >10%‐50%, or >50% Black residents) of each census tract. Logistic regression models with robust standard errors to account for clustering at the census tract modelled the association of walkability and cognitive impairment with adjustment for participant age, sex, years of education, marital status, race, and tract area deprivation index. Multiplicative terms were included in the models to test interactions of walkability with either population density or racial composition. Models were stratified when interaction p‐values <0.1.

Results

In adjusted analyses, walkability was not related to cognitive impairment in the full sample (OR = 0.89 (95% CI: 0.61‐1.28 for highest vs lowest quartile). Walkability interacted with population density (p interaction = 0.09 for highest vs lowest quartile), such that low walkability was associated with greater likelihood of cognitive impairment, but only in areas with high population density (OR = 1.85 (95% CI: 1.08‐3.17 for highest vs lowest quartile; Figure). There was no interaction with racial composition.

Conclusions

Neighborhood walkability may be an important population‐level modifiable risk factor for cognitive impairment but accounting for geographic context such as urbanicity is important for considering implications and interventions.
Anticholinergic burden and cognitive decline: findings from the ELSA‐Brasil cohort study
Authors: dos Santos Adriana Nancy Medeiros , Gonçalves Natalia G , Goulart Alessandra C. , Viana Maria Carmen , Lotufo Paulo A , Bensenor Isabela M , Suemoto Claudia Kimie
Published: January 2025

Background

Using multiple drugs with anticholinergic properties is common and might lead to cumulative anticholinergic toxicity and increased risk of cognitive decline. The cumulative adverse effects of anticholinergic medications that a person takes are called the “anticholinergic burden”. We hypothesized that a high anticholinergic burden may be a risk factor for cognitive decline. We aimed to investigate the longitudinal association between Anticholinergic Cognitive Burden (ACB) and cognitive decline in the ELSA‐Brasil study during eight years of follow‐up.

Method

Participants were evaluated in three study waves (2008‐2010, 2012‐2014, and 2017‐2019). The ACB was calculated based on the medications in use. Cognitive performance was evaluated using a standardized battery of tests (immediate recall, late recall, recognition, semantic and phonemic verbal fluency, and the trail‐making tests). A global composite z‐score was derived from these tests. The association of ACB with cognitive performance over time was evaluated using linear mixed‐effects models, adjusted for sociodemographic and clinical variables.

Result

A total of 15,105 participants were recruited and 2,040 were excluded, leaving 13,065 participants whose data were analyzed. Participants had a mean age of 51.7±9.0 years old, 55% were women, and 53% were white. During the follow‐up time, the ACB burden was associated with a decline in global cognition (β = ‐0.001, 95% CI = ‐0.013, ‐0.002, p = 0.004), memory performance (β = ‐0.002, 95% CI = ‐0.002, 0.000, p = 0.044) and executive function (β = ‐0.002, 95% CI = ‐0.004, 0.000, p = 0.014).

Conclusion

During eight years of follow‐up, the ACB burden was associated with cognitive decline, particularly in the memory and executive function domains.
Similarity of regional brain blood flow and glucose utilization imaging biomarkers in older adults
Authors: Lepping Rebecca J , Taylor Jasmine M , Honea Robyn A , Hess Benjamin J , Vidoni Eric D , Brooks William M , Burns Jeffrey M , Swerdlow Russell H
Published: January 2025

Background

Cerebral blood flow (CBF) and glucose utilization have both proven sensitive biomarkers of brain function in Alzheimer’s disease. However, while blood flow supplies glucose to cells to meet local demand, and therefore, are inter‐related, the two aspects are physiologically distinct. Our goal was to conduct a region‐to‐region correlation of magnetic resonance imaging (MRI) and 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) biomarkers of cerebral blood flow and glucose utilization to determine whether these physiologically distinct biomarkers yield functionally distinct information.

Method

108 older adults who were cognitively unimpaired (n=71), or had mild cognitive impairment (n=17) or dementia due to Alzheimer’s disease (n=18), and who were enrolled in the KUMC Alzheimer’s Center Cohort completed both MRI T1‐weighted structural and pseudocontinuous arterial spin labelling (PCASL) and FDG‐PET scanning. Participant‐unique brain regions were created by segmentation of the T1‐weighted images with FreeSurfer, combined into large regions of interest for anterior/posterior cingulate, frontal, temporal, and parietal cortices. Preprocessing in SPM12 and AFNI were conducted for the PCASL and FDG‐PET data separately, and regional CBF and glucose utilization (specific uptake value ratio [SUVR]) were extracted. Correlation analysis was conducted in SPSS 29.

Result

CBF and FDG‐PET SUVR were significantly positively correlated in the ACC‐PCC (r=.22, p=.02), Temporal (r=.26, p<.01), and Parietal (r=.37, p<.001) cortices, but not in the Frontal cortex (r=.13, p=.19). The correlations were modest, with the largest at .37 in Parietal cortex.

Conclusion

Our results indicate an expected, yet somewhat modest correlation in the majority compared regions. Additionally, the correlation was not identical across the brain, and non‐significant in frontal regions. This analysis revealed that CBF and FDG‐PET are complementary measures that provide non‐overlapping information. We conclude that these two biomarkers yield unique information and may have unique value in elucidating the relationship between blood flow and neuronal function, potentially more so for frontal rather than parietal regions.