bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare Expenditures among US Immigrants with Cognitive Limitations or Alzheimer’s Disease and Related Dementias
Authors: Jang Seyeon , Qin Xuanzi , Park Sungchul , McCoy Rozalina G. , Chen Jie
Published: January 2025

Background

Despite the growing number and proportion of the immigrant population in the US, there is a lack of knowledge on healthcare expenditures among immigrants with cognitive limitations or Alzheimer’s disease and related dementias (ADRD). This study estimated differences in total healthcare expenditures between US‐born and foreign‐born individuals by the presence of ADRD and/or cognitive limitations. This study also examined the differences in healthcare expenditures by service types, including inpatient stays, office‐based visits, emergency department (ED) visits, home healthcare, and prescription drugs.

Method

The study used nationally representative data from the 2007‐2020 Medical Expenditure Panel Survey (MEPS). Generalized linear regression models were used to estimate differences in healthcare expenditures between US‐born and foreign‐born individuals with ADRD, cognitive limitations without ADRD, and without ADRD or cognitive limitations. Analyses were also implemented by the immigrants’ duration of residence in the US, classified as foreign‐born living less than 10 years in the US and more than 10 years in the US. The study sample included all community‐dwelling adult Americans and had separate subpopulation analyses on the elderly population aged 65 and above. Survey weights were applied to all estimates.

Result

Foreign‐born individuals with cognitive limitations or ADRD had substantially higher total healthcare expenditures than their counterparts. Compared to US‐born individuals with ADRD, foreign‐born individuals with ADRD spent significantly more on home healthcare ($4,456.1, p = 0.029). Among individuals without ADRD or cognitive limitations, foreign‐born individuals spent significantly less than their US‐born counterparts in most healthcare services. Compared to their US‐born counterparts, immigrants with ADRD who had lived in the US for more than 10 years encountered significantly higher home healthcare costs ($4,245.6, p = 0.031), whereas those who had lived in the US for less than 10 years incurred significantly lower costs on office‐based visits (‐$1,833.8, p<0.001) and ED visits (‐$514.4, p<0.001). In contrast, immigrants with no ADRD and cognitive limitations spent significantly less than their US‐born counterparts on healthcare regardless of residence duration in the US.

Conclusion

Foreign‐born individuals with cognitive limitations or ADRD had substantially higher total healthcare expenditures than their US‐born counterparts, while foreign‐born individuals without ADRD or cognitive limitations spent significantly less than their US‐born counterparts.
An Investigation into The Role of Lifestyle Factors in SuperAgers
Authors: Watson Philippa , Koychev Ivan , Gallacher John , Bauermeister Sarah
Published: January 2025

Background

It is widely acknowledged that cognitive abilities tend to decline with age; however, there exists considerable intra‐individual variability in the rate of decline. While many individuals report varying degrees of cognitive decline, a small subset known as “SuperAgers” exhibits cognitive abilities comparable to those several decades younger. Our understanding of which factors enable SuperAgers to maintain their superior cognitive abilities is inconclusive. It is hypothesized, however, that the factors safeguarding against cognitive decline may also play a role in maintaining exceptional cognitive abilities.

Method

This study leverages data collected during Phase 5 (1997‐1999) and Phase 12 (2015‐2016) of the Whitehall II cohort, a longitudinal study focusing on British civil servants. SuperAgers were defined as those over 65 years old at Phase 12 who scored in the top tercile for verbal memory performance in Phase 12 and who performed above the mean for verbal memory at Phase 5. Structural equation modelling will be employed to conduct a multivariate statistical analysis investigating the association between engagement in various lifestyle factors (e.g., mental health, physical activity, social engagement, and biomedical factors) in SuperAgers and cognitively normal agers (CN’s).

Result

The study comprised 1,963 participants (511 females), with 812 meeting the criteria for SuperAgers and 1,156 for CN’s. SuperAgers exhibited lower levels of hypertension (t = 5.13, p < .001), medications (t = 2.86, p = .002), BMI (t = 1.79, p = .04), and higher engagement in high social activities (t = 3.44, p < .001), low social activities (t = 2.90, p = .002), and vigorous physical activities (t = ‐2.00, p = .02). No significant differences were observed between SuperAgers and CN’s regarding smoker status, alcohol consumption, sleep duration, mental health, and cardiovascular diseases (p > .05). Additional analyses are ongoing and will be completed by the conference date.

Conclusion

The findings from this study will provide valuable insights into the contribution and significance of various modifiable lifestyle factors in preserving cognitive function during older age.
Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals
Authors: Yang Liu , Yu Jin‐Tai
Published: January 2025

Background

Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms.

Method

This population‐based cohort included 43,1834 non‐demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen‐carrying indices, metabolites, and brain structures.

Result

During a follow‐up of 3,736,181 person‐years (mean follow‐up 8.65 years), 5,622 participants (1.30%) developed all‐cause dementia, which consisted of 2,511 Alzheimer’s dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all‐cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95%CI], 1.24 [1.14‐1.34], P = 1.10 × 10−07; forced vital capacity [liter]: 1.16 [1.08‐1.24], P = 2.04 × 10−05; peak expiratory flow [liter/min]: 1.0013 [1.0010‐1.0017], P = 2.73 × 10−13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen‐carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function.

Conclusion

Life‐course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.
Resting‐state brain activity and association with baseline physical activity
Authors: Koromila Georgia , Faraza Sofia , Dyrba Martin , Wolf Dominik , Fischer Florian U , Knaepen Kristel , Kollmann Bianca , Binder Harald , Mierau Andreas , Riedel David , Fellgiebel Andreas , Tüscher Oliver , Teipel Stefan
Published: January 2025

Background

Normal aging is associated with alterations of functional connectivity (FC) in brain neuronal networks. Altered network connectivity may be associated with accelerated cognitive decline. Physical activity is considered a beneficial lifestyle factor for maintaining cognitive health. Higher intensities of physical activity may induce structural and functional changes in the brain, particularly in regions involved in cognitive functions, such as memory, attention and executive functions. However, the underlying neural mechanisms are not widely investigated. Our aim was to examine the association between resting‐state FC of brain networks and baseline physical activity in healthy older adults.

Method

We analyzed baseline resting‐state fMRI and baseline physical activity data of 149 healthy older adults (mean age: 68 years) from the AgeGain study. Physical activity was measured by using actigraphs worn for 7 days. Different intensities were measured, such as light, mean and moderate‐to‐vigorous activity (min/d). We used Independent Component Analysis (ICA) and seed‐based approaches to examine brain network activity in the Default Mode Network (DMN), Salience Network (SAL), Central Executive Network (CEN), Visual Network (VN) for cognitive effects and Sensorimotor Network (SMN) for physical effects.

Result

We observed statistically significant associations between functional activation within SMN and light physical activity and spatially restricted effects for DMN and moderate‐to‐vigorous physical activity (p <.01 uncorrected). In addition, we observed an overlap on frontal activation across DMN, SMN and SAL. Results of the seed‐based analysis will be presented at the conference.

Conclusion

Light to higher intensities of physical activity showed an association with higher functional activation of networks previously associated with cognitive decline and physical activity. This agrees with the notion that physical activity may be a protective factor against cognitive decline. Further research is needed to test the replicability of these results.
Effect of combination treatment with escitalopram and risperidone in punding behaviour among patients with dementia‐ a retrospective study
Authors: Tripathi Shailendra Mohan , Shahi Mohit Kumar , Chutia Porimita
Published: January 2025

Introduction

Punding is a unique stereotypical, repetitive, non‐goal‐directed behavior characterized by an intense fascination with daily objects. This behavior although commonly seen in dementia patients is relatively less studied. In this study, we aimed to assess the effectiveness of combination treatment of escitalopram and risperidone treatment in the punding behavior of dementia patients.

Methodology

A retrospective study of dementia patients with punding behavior treated inpatient with a combination treatment of escitalopram and risperidone from January 2023 to October 2023. A semi‐structured proforma was used to collect the demographic details, illness information, and outcomes based on standardized rating scales from the records of a tertiary care center in India. The data were analyzed using paired t‐test and McNemar test.

Results

A total of 29 patients, 17 females and 12 males with a mean age of 74.14 ± 7.18 years were included. A significant decline was found in the Neuropsychiatric Inventory (NPI) motor behavior subscale score and caregiver distress related to motor behavior from Day 0 to Day 7 (p‐value of 0.0002, p = 0.001) on the combination treatment. However, the total NPI Severity Score and total QUIP‐RP Score (for repetitive behavior) exhibited a reduction in scores from Day 0 to Day 7 but the p‐value was non‐significant.

Conclusion

The study adds valuable insights into the management of punding behavior and its associated distress providing a basis for further research on the neurobiological underpinnings of this distinctive symptom in dementia.
Cognitive Screening of Community‐Dwelling Older Adults in Shanghai Using a Game‐based Mobile Screening Tool: A Cross‐Sectional Study
Authors: Wu Jingnan , Zhou Zhixing , Xia Huanhuan , Chen Nan , Li Yatian
Published: January 2025

Background

Game‐based Cognitive Assessment – 3‐minute Version (G3) is a self‐administrated mobile screening tool for detecting early cognitive impairments among Chinses community‐dwelling older adults. Released as a WeChat and Alipay mini‐programs, G3 offers a convenient and cost‐free means for individuals to evaluate their cognitive functions online. This study aimed to investigate the cognitive performance of older adults in the Shanghai community with G3. Additionally, a comparison was made between the cognitive performance of older adults who participated in the screening offline and those who proactively participated online.

Method

Between June and October 2023, an offline cognitive screening with G3 tests was performed in Xiaodongmen subdistrict of Shanghai. And G3 results of 3344 participants aged 55‐89 years old were enrolled for restrictive analysis. Simultaneously, G3 online assessment records between January and December 2022 completed by 64535 individuals aged 55‐89 years old from various regions of China, were reviewed and compared to the offline screening results.

Result

Among older adults aged 55 to 89 in Xiaodongmen communities, the average G3 score (mean ± stand deviation) was 56.82±12.47. Furthermore, the mean G3 score for males and females was 57.23±12.29 (n = 1569) and 56.46±12.61(n = 1775), respectively, both of which exhibited a trend of cognitive decline with increasing age (Figure 1). Moreover, older adults with a high school education or higher demonstrated significantly better cognitive performance compared to those without (p<0.05, Figure 2). When comparing the online self‐administrated G3 results of age‐matched older adults, both cohorts displayed a similar trend of cognitive decline with increasing age. However, the average G3 score obtained from Xiaodongmen subdistrict was statistically lower than that of the online assessments (p<0.05, Figure 3).

Conclusion

This study characterized the cognitive function among older adults in Shanghai and enhanced the feasibility of G3 tool for large‐scale cognitive screening in Chinese communities. Nonetheless, due to the notable disparity between online and offline screening results, further investigations are warranted to explore the underlying mechanisms.
AAV9‐SORL1 gene therapy for Alzheimer’s disease
Authors: Andersen Olav M. , Qureshi Yasir H. , Jensen Anne Mette Gissel , Williams Andrew , Young Jessica E. , Roy Mimi , Klein Joel , Armstrong Rob , Merchant Kalpana M.
Published: January 2025

Background

Convergent evidence indicates that deficits in the endosomal recycling pathway underlies pathogenesis of Alzheimer’s disease (AD). SORL1 encodes the retromer‐associated receptor SORLA that plays an essential role in recycling of AD‐associated cargos such as the amyloid precursor protein and the glutamatergic AMPA receptor. Importantly, loss of function pathogenic SORL1 variants are associated with AD. Moreover, both SORLA and retromer protein levels are reduced in the most vulnerable regions of AD brains. Thus, restoration of SORLA levels and function via viral transduction is an attractive therapeutic strategy. Unfortunately, the full‐length SORL1 is too large to be packaged into a viral capsid for gene therapy.

Method

We identified and tested endosomal recycling effects of a truncated SORL1 mini‐gene construct after transient transfections in HEK293 cells. We developed a gene therapy lead by packaging SORL1 mini‐gene into AAV9. This lead was tested for expression and activity in neurons differentiated from human induced pluripotent cells (hiPSC) as well as in vivo after brain infusions in wild‐type mice and SORL1 haploinsufficient Göttingen minipigs by biochemistry and immunohistochemistry.

Result

Expression of the SORL1 mini‐gene in HEK293 cells increased endosomal recycling of full‐length SORLA as shown by elevated cell surface expression and shedding of the SORLA mini receptor. In hiPSC neurons, AAV9‐SORL1 treatment resulted in strong endosomal expression of the SORLA mini‐receptor that co‐localized with components of the retromer complex in endosomes. In vivo, we observed dose‐dependent transduction and expression of SORLA mini‐receptor in neurons, which localized to endosome‐like punctate structures. Evaluation of functional effects is underway.

Conclusion

We conclude that the AAV9‐SORL1 mini‐gene expresses SORLA mini‐receptor in neurons which resides in intracellular vesicular endosomal structures together with the retromer complex and has the capacity to boost the endosomal recycling pathway. Thus, the SORL1 mini‐gene is a promising candidate for gene‐therapy for AD patients.
The influence of the adherence on intervention effect: J‐MINT study
Authors: Uchida Kazuaki , Sugimoto Taiki , Matsumoto Nanae , Fujita Kosuke , Yokoyama Yoko , Kuroda Yujiro , Sakurai Takashi , Arai Hidenori
Published: January 2025

Background

This study aimed to examine the influence of adherence on intervention effect in the Japan‐multimodal intervention trial for the prevention of dementia (J‐MINT).

Method

J‐MINT was an 18‐month randomized controlled trial, and participants aged 65‐85 years with mild cognitive deficits were randomized into multidomain intervention (physical exercise, nutritional counseling, cognitive training, and vascular risk factor management) and control groups. This study included the participants in J‐MINT who had undergone the intervention program and follow‐up evaluation at least once. Adherence in each intervention component was classified as adherent (1 point) or non‐adherent (0 point), and the total score was calculated (score range: 0‐4 points). Adherent was defined as follows: the adherence rate to group‐based physical exercise ≥ 70%, the number of nutritional counseling ≥ 14 times, the number of days of cognitive training ≥ 156 days, and those who have blood pressure, glucose levels, and cholesterol within the target range. Three groups were created based on the total score: adherent group (4 points), partially adherent group (2‐3 points), and non‐adherent group (0‐1 points). The outcome was the changes in composite score calculated by eight neuropsychological tests from baseline to 18 months, including tests of global cognitive function, memory, attention, and executive function/processing speed. Mixed models for repeated measures were used to calculate mean differences (MD) of outcome between each adherence and control group.

Result

Out of 531 participants enrolled in J‐MINT, 421 participants (mean age: 73.8 years, 52% female) were included. The number of participants in the adherence group was 9 in the adherent group, 163 in the partially‐adherent group, and 31 in the non‐adherent group. Statistical analysis showed that the adherent group exhibited a significant interventional effect compared to the control group (MD = 0.266, p = 0.025), while no significant mean difference was observed between the other adherence group and the control group.

Conclusion

Our findings suggest that supporting adherence is important to achieve the sufficient effect of multidomain interventions.
Biomarker‐guided clustering in an Amish population older than 60 reveals subgroups featuring distinct Alzheimer Disease pathologies
Authors: Wang Ping , Song Yeunjoo E. , Lynn Audrey , Miskimen Kristy L. , Prough Michael B. , Dorfsman Daniel A. , Gulyayev Alex V. , Laux Renee A. , Fuzzell Sarada L. , Hochstetler Sherri D. , Zaman Andrew F , Adams Larry D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Whitehead Patrice L. , Liu Yining , Moore Noel C. , Main Leighanne R. , Ogrocki Paula K. , Lerner Alan J. , Griswold Anthony J. , Vance Jeffery M. , Cuccaro Michael L. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L.
Published: January 2025

Background

Plasma amyloid‐beta (Aβ) 42/40 ratio and phosphorylated tau 181 (pTau181) are promising blood biomarkers for AD. Compared to heterogenous clinical phenotypes, they are more objective and proximal to the pathological hallmarks of Aβ plaques and tau tangles. Biomarker‐guided clustering using Aβ42/40 and pTau181 can potentially establish subpopulations that share similar mechanisms of AD and treatment responses.

Method

Plasma biomarkers were measured using Simoa™ Neuro‐3Plex, 4Plex, and pTau181 Advantage V2 assays. To eliminate potential confounding effects, age, sex, and study center were regressed out of Aβ42/40 and pTau181 using a quadratic regression model. Adjusted biomarkers were then normalized for unsupervised K‐means clustering, with the optimal number of clusters determined by the elbow method and Silhouette score. To interpret the cluster profiles, we explored the differences in demographics and clinical features between clusters. We also examined the association between clusters and neuropsychological tests adjusting for age, sex, study center, APOE e4 alleles, and diagnosis.

Result

We analyzed plasma biomarkers from 593 Amish individuals (age ³ 60 years old) living in Ohio and Indiana. 62% were females, and the average age was 81.7 ± 5.7 years. Utilizing plasma Aβ42/40 and pTau181, the clustering approach yielded six distinct clusters (N = 92, 95, 94, 152, 75, and 85) whose composition was driven by varying burdens of amyloid and tau pathology. There was no significant difference in proportion of cognitive impairment or of family structure across clusters. As expected, the low Aβ42/40 and high ptau cluster (Cluster 6) featured a significantly higher proportion of APOE e4 carriers than other clusters combined (51% vs 22%, p = 0.002). No significant associations were found between clusters and neuropsychological tests.

Conclusion

The integrated analysis of plasma Aβ42/40 and pTau181 in the Amish established six clusters with varying levels of amyloid and tau burden, suggesting possible differences that need to be further explored. Examination of potential genetic or pathophysiological differences across the clusters are underway.
Exposure Severity and Cognitive Dysfunction are Mediated by Low‐Grade Cerebral Amyloidosis: A PET/MRI study of World Trade Center responders
Authors: Kritikos Minos , Zhou Juin W. , Huang Chuan , Vaska Paul , Clouston Sean A.P. , Luft Benjamin J
Published: January 2025

Background

World Trade Center (WTC) responders endured exposures to neurotoxic dust particulate matter. This neuroimaging study examined the presence of amyloidosis in Alzheimer’s disease (AD) regions of interest (ROIs) and associations with exposure duration.

Method

Simultaneous positron‐emission tomography with [18F]‐florbetaben and magnetic resonance neuroimaging was acquired on 34 middle aged WTC responders. Centiloid scale used mean standardized uptake value ratio (SUVR) with between subjects comparisons of cognitively unimpaired (n=17) and early‐onset dementia (n=17) responders. Pathway analyses investigated potential neuropathological cascades.

Result

Only one subject was Centiloid positive. However, considerable SUVRs in non‐AD ROIs associated with changes in cortical mean diffusivity, cortical thickness, cognition, and exposure duration, mediated by the olfactory bulb.

Conclusion

Fibrillar amyloidosis may have originated in, and spread from the olfactory cortex because of prolonged exposures to WTC neurotoxic dust. Our study also identifies a non‐AD neuropathological topology of amyloidosis, which associated with lower measures of brain health.
Soda consumption and risk of dementia: The Northern Manhattan Study
Authors: Farhi Arielle , Rundek Tatjana , Agudelo Christian , Elfassy Tali , Wright Clinton B. , Elkind Mitchell S.V. , Gutierrez Jose , Gardener Hannah
Published: January 2025

Background

Soda consumption has been associated with vascular risk factors and events. While diet quality is understood to impact dementia risk, little is known about soda consumption in relation to dementia. We hypothesized that regular soda and diet soda consumption were associated with an increased dementia risk.

Method

We utilized data from 959 participants in the Northern Manhattan study, a longitudinal population‐based multi‐ethnic cohort. Regular and diet soda consumption were assessed by food frequency questionnaire at baseline (1993‐2001) and examined continuously (sodas/week) and categorically. Incident dementia was adjudicated during follow‐up after a series of comprehensive neuropsychological and clinical assessments. We used logistic regression models to examine the associations between regular and diet soda consumption and risk of dementia, adjusting for demographics and vascular risk factors (body mass index, diet quality, smoking history, alcohol use, physical activity level).

Result

Of 959 participants with recorded data on soda intake and neuropsychological assessments (mean baseline age 64±8 years, 40% men, 64% Hispanic, 16% non‐Hispanic White, 18% non‐Hispanic Black), 174 (18%) developed dementia over an average of 11 years of follow‐up. 4.9% of participants drank regular soda >1/day and 2.3% of participants drank diet soda >1/day. Consumption of diet soda was associated with an increased risk of dementia (diet soda/week OR = 1.04, 95% CI 1.00‐1.08), adjusting for sociodemographics and vascular risk factors. Those who consumed more than one diet soda per day had a 3.91‐fold increased risk compared to <1/day (95% CI 1.31‐11.63), and this association was especially strong for non‐Hispanic Black participants (OR = 10.01, p<0.05). The association was not apparent after excluding those with obesity or the metabolic syndrome (N = 476, diet soda/week OR = 1.03, 0.94‐1.13). An association between regular soda consumption and incident dementia was only observed after excluding those with obesity or the metabolic syndrome (regular soda/week full cohort: 1.01, 0.98‐1.04; restricted cohort: OR = 1.05, 1.00‐1.10).

Conclusion

The results support a potential increased risk of dementia associated with frequent consumption of regular and diet soda, but further research is needed in diverse study populations, with great attention paid to the confounding and mediating impacts of cardiometabolic risk factors and the potential for effect modification by race.
Social Vulnerability Index and Cognitive Decline in a Population‐Based Cohort Study
Authors: Desai Pankaja , Ng Ted K.S. , Krueger Kristin R , Evans Denis A , Rajan Kumar B
Published: January 2025

Background

Social determinants of health (SDOH) are critically important to reduce disparities in Alzheimer’s disease (AD). Yet, we often focus on individual‐level characteristics, excluding socio‐environmental factors, when evaluating predictors of AD or developing interventions that target AD prevention. To address these gaps, we examine the association between the social vulnerability index (SVI) and cognitive decline in a bi‐racial cohort of older adults.

Method

In this investigation, we use data from participants (N = 6,763) in the Chicago Health and Aging Project (CHAP), a longitudinal, population‐based cohort study in four south‐side Chicago communities. The study sample consists of participants who completed at least two neuropsychological assessments approximately three years apart. SVI is a score which utilizes US Census data to measure certain SDOH and calculates percentile rankings by census tract. Linear mixed effects regression models examined the association between SVI and cognitive decline, adjusting for age, sex, race, and education.

Result

The study sample comprised of more AA (63%) and female (61%) participants. The greatest percentage of AA participants were represented in quartile 3, and the greatest percentage of White participants were represented in quartile 1. We found that participants living in communities with greater SVI had more rapid global cognitive decline (quartile 2 (β = ‐0.010, SE = 0.005, p = 0.05), quartile 3 (β = ‐0.010, SE = 0.004 p = 0.024), and quartile 4 (β = ‐0.014, SE = 0.005, p = 0.005) compared to participants living in the lowest SVI communities.

Conclusion

Social vulnerability plays a crucial role in faster cognitive decline, thereby increasing AD risk in more vulnerable areas. Reducing social vulnerability in communities might help reduce the future risk of AD.
Nutritional influences on Alzheimer’s disease: Insights from transformer models and explainable AI
Authors: Liu Ziming , Liu Longjian , Heidel Robert , Zhao Xiaopeng
Published: January 2025

Background

This study utilizes transformer‐based machine learning models and explainable AI (XAI) techniques to investigate the complex relationship between various nutritional factors and AD mortality. Drawing data from the Third National Health and Nutrition Examination Survey (NHANES III 1988 to 1994) and the NHANES III Mortality‐Linked File (2019), it aims to dissect the multifaceted interactions between nutrition and AD.

Method

The study employs advanced transformer models alongside traditional machine learning methods like random forests and support vector machines. These models are applied to the NHANES III dataset to predict mortality outcomes in AD, HD, and CA, with a particular focus on nutritional factors. XAI techniques, including the Shapley Additive Explanations (SHAP) and integrated gradients, are used to enhance the interpretability of these models. The aim is to identify and understand the most influential nutritional elements contributing to AD mortality and how these compare across different disease contexts.

Result

Transformer models demonstrated a high degree of accuracy and reliability in identifying AD cases, outperforming traditional models in recall scores. XAI analysis highlighted several key nutritional factors significantly associated with AD mortality, such as serum apolipoprotein AI, vitamin B12, and selenium levels. These findings underscore the potential of transformer models and XAI in extracting deeper insights from complex medical data. Additionally, the study revealed distinct nutritional patterns associated with AD compared to HD and CA, suggesting specific nutritional pathways influencing the progression and mortality of these diseases.

Conclusion

This research represents a significant step forward in applying advanced AI methodologies to medical research, particularly in the context of AD. By leveraging transformer models and XAI, the study provides a nuanced understanding of the impact of nutrition on AD mortality. It highlights the potential of these techniques in unraveling the complex interplay between diet and disease progression, offering a foundation for future investigations into targeted nutritional interventions for AD management. The findings also suggest broader implications for the use of AI in healthcare, paving the way for more sophisticated and personalized approaches to disease prevention and management.
Towards improved dementia prediction in the population: accounting for peripheral factors associated with levels of AD biomarkers
Authors: Hu Yi‐Han , Meirelles Osorio , Satizabal Claudia L , Gudnason Vilmundur , Tracy Russell P. , Seshadri Sudha , Launer Lenore J.
Published: January 2025

Background

Blood‐based biomarkers, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), show potential for dementia risk stratification. Yet, their predictive performance for incident dementia in heterogeneous older population with multi‐morbidities, is not well tested. This study evaluates their predictive ability for incident dementia accounting for differences in factors affecting health.

Method

Data from 910 baseline non‐demented participants of the population‐based Age, Gene/Environment Susceptibility‐Reykjavik Study (AGES‐RS) from 2002 to 2015 (average age 76.6 years, 54.2% female, 6.7% incident dementia) were analyzed. Factors (n = 360) (sociodemographic, clinical, sensory, cardiometabolic, musculoskeletal, medical history, and lifestyle) clustered into 34 groups. Incident dementia cases were identified following the baseline exam until December 2015. Logistic regression models, with 5000 bootstraps, evaluated the predictive power of GFAP and NfL for incident dementia. Predictor sets included: biomarker only; plus age and sex; plus basic factors (education, APOE e4, eGFR); and a full model with associated peripheral clusters. An additional model with age and sex served as the reference for assessing performance without biomarker. Model effectiveness was assessed using area under the precision‐recall curve (AUPRC), precision, and sensitivity (recall), suitable for low dementia prevalence contexts.

Result

Biomarker levels between cases and non‐cases showed significant overlap (Figure 1a). In predictive performance for incident dementia, NfL outperformed GFAP in the biomarker‐only model (AUPRCs, GFAP: 0.17, NfL: 0.20). Integrating peripheral clusters associated with these biomarkers improved the models’ performance, surpassing both biomarker‐only and basic models, especially for NfL (Figure 1b). Precision rates for the final GFAP and NfL models were 0.304 and 0.61, respectively, reflecting approximately 30% and 61% prediction accuracy for incident dementia. The GFAP’s AUPRC improved to 0.339, accurately identifying 5 out of 100 incident dementia cases, while the NfL’s AUPRC was 0.367, predicted 17% of cases.

Conclusion

Our findings indicate that due to the low prevalence of dementia in the general population, using plasma GFAP and NfL as dementia screening tools is not highly effective. However, the addition of peripheral factor clusters does enhance their predictive performance, with NfL having a slightly better performance over GFAP.
Development of Xanamem, an isoform 1 specific inhibitor of 11‐βHSD, as a procognitive and disease modifying treatment for mild/moderate Alzheimer’s disease. A pharmacodynamic and biomarker driven approach
Authors: Rolan Paul , Taylor Jack , Seckl Jonathan , Harrison John E , Chen Christopher Li‐Hsian , Farrell Colm , Maruff Paul , Woodward Michael , Hilt Dana
Published: January 2025

Background

Selecting the optimal dose for clinical development is especially problematic for drugs directed at CNS‐specific targets. For drugs with a novel mechanism of action, these problems are often greater. We describe Xanamem’s clinical pharmacology, including the approach to dose selection and proof‐of‐concept studies. Xanamem is an isoform 1 specific inhibitor of 11‐βHSD which acts to reduce the tissue production of cortisol. Xanamem is under clinical development as a pro‐cognitive and disease modifying drug for Alzheimer’s disease as well as other neurological and psychiatric diseases involving CNS dysregulation of cortisol. Elevation of CNS cortisol has been associated with impaired cognition, neuroinflammation, and neuronal death.

Method

Clinical pharmacology analyses included pharmacokinetic and pharmacodynamic data from SAD and MAD dose trials in healthy volunteers; population pharmacokinetics; cognition from patients in a phase 2a trial in Alzheimer’s disease; multiple dose PET target occupancy study to determine target inhibition in the brain in healthy elderly participants and Alzheimer’s patients; two phase 1b trials in healthy older participants that assessed safety; and pharmacodynamic endocrinology and quantitative cognitive parameters.

Result

Xanamem demonstrated high CNS target occupancy at all doses studied by PET (5‐30 mg/day). At doses of 5 to 70 mg/day ACTH levels approximately doubled at steady‐state. After first doses, plasma cortisol was slightly reduced but was not decreased at steady‐state in doses of ≤ 10mg/day but was within normal levels. In three trials Xanamem demonstrated pro‐cognitive effects, primarily on attention and working memory (5‐20 mg/day). Xanamem also demonstrated potentially disease modifying treatment effects in mild AD in patients with biomarker positive AD (elevation of plasma pTau181) as shown by decrease in the rate of CDR‐SB worsening over 12 weeks (10 mg/day) versus placebo.

Conclusion

This series of trials demonstrates that the optimal dose of Xanamem can be selected based on CNS PET occupancy data coupled with pharmacodynamic endocrinology and quantitative cognition testing. Pro‐cognitive and potentially disease modifying effects were observed at doses consistent with high CNS target occupancy. Xanamem is now in larger Phase 2 clinical outcome trials in MDD and mild/mod AD.
Comprehensive lipidomic analysis for identification of lipid biomarkers associated with Alzheimer´s disease
Authors: Wretlind Asger , Xu Jin , Proitsi Petroula , Legido‐Quigley Cristina
Published: January 2025

Background

Alzheimer’s disease (AD) is a devastating disease at an individual level and for the wider society. Despite huge research efforts the underlaying causes of AD is still not well understood. We know that lipid metabolism is fundamental for maintaining a heathy brain and that some of the strongest risk factors for AD, such as APOE4, affect lipids. In this study we set out to measure the lipid changes associated with AD.

Method

We used a total of 841 participants from the AddNeuroMed and Dementia Case Register cohorts: 306 people with AD, 165 people with mild cognitive impairment (MCI) (n = 165), and 370 healthy controls.

Mass spectrometry based lipidomics was carried out on plasma samples using a Waters ACQUITY UPLC and XEVO QTOF‐MS.

Lipid molecules were clustered into modules based on correlation networks using Weighted Gene Correlation Network Analysis (WGCNA). Module eigengenes were used to investigate the association of each module with MCI and AD. Key lipid drivers (‘Hub’) associated with AD were selected and investigated further. Linear regression analyses were used to investigate the association of modules and key lipids with AD and MCI status after adjustment for sampling site, age, sex and presence of APOE4 allele. The False Discovery Rate (FDR) was applied to control for multiple testing.

Result

Lipidomics analysis resulted in 261 identified lipid molecules, which were analyzed with WGCNA resulting in 10 robust modules. Four modules were significantly associated with AD vs. healthy control after adjusting for covariates and following correction for multiple testing. Investigating the lipid drivers of these modules highlighted 55 lipid hubs, 26 of which were significantly associated with AD vs. control, after adjustment for confounders and multiple testing. These lipids included triglycerides, phosphatidylcholines, phosphatidylethanolamines and lysophosphatidylcholines.

Conclusion

Here, we present a workflow for robust identification of lipid molecules associated with Alzheimer’s disease. Further work will establish how these lipids relate to AD risk factors, clinical measures, and genetic risk for AD.
“My Wife and I Invariably Go Together”: A Mixed Methods Analysis of Physical Activity and its Influences on Older Adult Dyads
Authors: Wales Jenny L , Hamilton Calum Alexander , McCarthy Louis , Bayat Sayeh , Tangen Gro Gujord , Ireson Neil , Lanfranchi Vita , Farina Nicolas , Hicks Ben , Ardle Ríona Mc
Published: January 2025

Background

Physical activity (PA) is an imperative factor to healthy cognitive and functional ageing and may act as a protective factor against cognitive decline. Evidence suggests that as we age, PA declines, leaving a large proportion of older adults (OAs) ‘underactive’ and ‘unprotected’. Socialisation/social support is considered a beneficial influence on PA in OAs. It is unclear whether dyadic (e.g. spousal) influences impact PA in healthy ageing, and how this might impact digital activity monitoring or intervention development to support prevention of cognitive decline. This research aims to quantify volume and types of PA and explore influential factors for PA participation in OAs.

Method

Participants were recruited via the ActivDyad study, where they wore a lumbar‐based‐accelerometer (AX6, Axivity) for 7 days, and completed a 7‐day activity diary. PA (i.e. daily steps) was derived from accelerometers using validated algorithms. Qualitative content analysis of the diaries was adopted for contextual understanding of the types and influences of PA. The Theoretical Domains Framework was utilised to identify common facilitators/barriers of PA in OAs.

Result

21 dyads (42 OAs) participated in the study; 10 dyads were included in preliminary analysis (mean age (mean±SD): 68.6±4.8; 100% heterosexual & married; mean relationship time: 45±10 years; 80% retired). Participants carried out an average of 15,680 daily steps (range: 7,243‐22,668), and indicated their most frequent PA as: shopping, gardening, housekeeping, and recreational walks (Table 1). Participants identified potential facilitators (Table 2) and barriers (Table 3) for partaking in PA. Social influence (e.g. partner) was identified as most influential; 75% of participants mentioned this as a facilitator for PA. Environmental context, particularly weather conditions, were frequently discussed as both a facilitator (50%) and barrier (45%) to PA.

Conclusion

Results suggest that dyadic interactions are a key facilitator of PA in OAs. Weather appears to have a bi‐conditional influence, promoting and/or discouraging PA; this may impact activity monitoring during adverse weather conditions (e.g. lower steps). Adherence may be higher in group PA interventions, and outdoor PA should be promoted in suitable weather. Analysis of the full sample will inform studies focusing activity monitoring and intervention development for dementia‐carer dyads.
Diurnal variation in blood‐based biomarkers for neurodegeneration and the circadian markers melatonin and cortisol in Alzheimer's
Authors: Monica Ciro della , Revell Victoria Louise , Atzori Giuseppe , Laban Rhiannon , Skene Simon S. , Heslegrave Amanda J , Hassanin Hana , Nilforooshan Ramin , Zetterberg Henrik , Dijk Derk‐Jan
Published: January 2025

Background

Disruption in diurnal rest‐activity rhythms is a hallmark of Alzheimer’s disease. Currently, we know little about how physiology, symptoms, and biomarkers change over the 24‐hour day in people living with Alzheimer’s disease. In particular, we don’t know whether plasma biomarkers of neurodegeneration, which offer promise as diagnostic or stratification tools, vary with time of day, and whether these associate with the circadian markers melatonin and cortisol.

Methods

We studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27‐hour laboratory protocol including a sleep episode with either two blood samples taken 12 hours apart (n = 17) or 3‐hourly blood sampling for 24 hours (n = 21). The participants were people living with mild Alzheimer’s disease (PLWA, n = 8), their partners/caregivers (n = 6), and cognitively intact older adults (n = 24). The neurodegeneration biomarkers phosphorylated tau (p‐tau217), amyloid‐beta 40 (Aβ40), amyloid‐beta 42 (Aβ42), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels were measured with single molecule array technology. A mixed linear model (PROC MIXED, SAS) was run to assess the impact of time‐of‐day, group, and any interaction. The gold‐standard markers of the circadian clock, plasma melatonin and cortisol, were measured using liquid chromatography mass spectrometry (LC‐MS) for the 24‐hour timeseries (n = 21). Correlations were run (R) to explore relationships between 24‐hour levels of dementia biomarkers, melatonin and cortisol.

Results

Diurnal rhythms in melatonin and cortisol were observed in all participant groups. Significant time of day variation was observed for p‐tau217, Aβ40, Aβ42, NfL, and a significant effect of group for p‐tau217 with highest levels in PLWA. There were no significant correlations between 24‐hour levels of melatonin or cortisol and any of the neurodegeneration biomarkers.

Conclusions

Time of day variation was observed in central circadian hormone markers and commonly used biomarkers of dementia in all participants. Outputs of the central circadian clock were not markedly altered in PLWA, and there was no relationship between 24‐hour levels of these outputs and blood‐based biomarkers of dementia. Time of day variation in biomarkers may be relevant to their implementation and interpretation in research and clinical practice.
The Emory‐Sage‐SGC‐JAX TREAT‐AD Center: Target Enabling Packages for Alzheimer’s Disease Emerging Targets
Authors: Leal Karina , Axtman Alison D. , Betarbet Ranjita , Brennan Paul E , Carter Gregory W , Fu Haian , Greenwood Anna K , Longo Frank M. , Edwards Aled M , Levey Allan I. , Center Emory‐Sage‐SGC‐Jax TREAT‐AD
Published: January 2025

Background

There is an urgent need for new therapeutic and diagnostic targets for Alzheimer’s disease (AD). Dementia afflicts roughly 55 million individuals worldwide, and the prevalence is increasing with longer lifespans and the absence of preventive therapies. Given the demonstrated heterogeneity of Alzheimer’s disease in biological and genetic components, it is critical to identify new therapeutic approaches. The Emory‐Sage‐SGC‐JAX TREAT‐AD Center is generating and openly distributing validated experimental tools necessary to test target predictions generated through sequence‐based characterization of human disease state. We believe that these tools and reagents, including chemical and biological probes that target the multifaceted dysregulation in the brains of AD patients, will advance the discovery of potential drug targets for AD.

Method

Our Center has focused on developing a robust target prioritization and target enabling package (TEP) development pipeline, where we not only produced, characterized, and validated key enabling reagents for dozens of potential AD drug targets for which there were few reagents, but also developed new approaches to expedite target prioritization and organization, antibody characterization, and chemical probe discovery. The current target portfolio was assembled by evaluating prioritized understudied proteins by the AMP‐AD consortium and additional NIA‐supported AD consortia. Nominated targets were evaluated by calculating an unbiased AD risk score and then mapped to 19 biological domains (BDs) that describe and codify the different processes that are dysregulated in AD and prioritized based on multiple lines of evidence for overall AD‐risk. Targets that meet criteria for development are evaluated to identify a set of experimental reagents necessary for hypothesis testing.

Result

We have prioritized more than 50 understudied targets for TEP development. For each understudied target, a TEP includes expression constructs, purified protein and methods, validated knockout cell lines, and antibody validation. For a subset of tractable targets additional TEP components include assay development, crystal structures, screening, and probe development. Advanced targets include SYK, DDX1, SDC4, ARHGEF2, and MDK.

Conclusion

All data, protocols, reagent sets, and chemical tools will be made widely available on the AD Knowledge Portal with no intellectual property claims. For more information see www.treatad.org.