bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the first TREM2 small molecule agonist, VG‐3927, for clinical development in Alzheimer’s disease
Authors: Mirescu Christian 
Published: January 2025

AbstractBackgroundTREM2 is a lipid‐sensing receptor expressed by microglial sub‐populations within neuropathological microenvironments, whose downstream signaling promotes microglial survival, plasticity, and migration. Multiple loss‐of‐function variants strongly implicate TREM2 as a key regulator of Alzheimer’s disease (AD) risk. Accordingly, TREM2 antibodies are currently in development to evaluate the therapeutic potential of TREM2 agonism in neurodegenerative diseases. Small molecule TREM2 agonist could represent a significant advancement for patients by providing potential key advantages in route of administration, superior brain penetration, and alternative mechanisms of action versus monoclonal antibodies. Herein, we share recent in vitro and in vivo preclinical data identifying VG‐3927, the first and only small molecule TREM2 agonist in clinical development as a potential disease‐modifying therapeutic.MethodThe agonist pharmacology of VG‐3927 was determined across an array of human cellular systems. Human iPSC‐derived microglia, astrocytes and neurons tri‐cultures were utilized to measure changes in microglia function and impact on neurodegeneration biomarkers in response to pharmacological and genetic modulation. Additionally, a humanized TREM2 amyloidosis mouse model (hTREM2‐5xFAD) was employed to determine the impact of VG‐3927 on AD‐associated neuropathological endpoints.ResultPharmacologic data suggest VG‐3927 is a highly potent, selective and brain penetrant TREM2 agonist with a favorable functional profile. In human tri‐cultures, VG‐3927 promoted anti‐inflammatory microglia activation and suppressed a broad spectrum of neurodegeneration‐associated biomarkers. Mutagenesis mapping studies demonstrated that the activity of VG‐3927 is on‐target, and results in functional effects via the coordinated clustering of TREM2. Following only 6 weeks of oral dosing in humanized TREM2 plaque‐bearing mice, VG‐3927 also reduced pathological forms of Aβ, insoluble ApoE levels, and peri‐plaque dystrophic neurites. Additional PKPD studies in non‐human primates further confirmed the brain penetrance and pharmacological activity in CNS.ConclusionVG‐3927 represents the first potent, selective small molecule TREM2 agonist able to favorably tune human microglia activation and impart a broadly neuroprotective profile across preclinical model systems. Initial PKPD studies have confirmed brain penetrance and pharmacological activity in CNS; an ongoing clinical study aims to further interrogate the potential of VG‐3927 as an AD modifying therapeutic with transformative potential as an orally bioavailable treatment.
Cardiovascular Health and Cognitive Function in Early Midlife: A Cross‐Sectional Analysis of the 1970 British Cohort Study
Authors: Chiesa Scott T , James Sarah‐Naomi , Hughes Alun D 
Published: January 2025

AbstractBackgroundPoor cardiovascular health in midlife increases risk of dementia in later years. At least some of this risk may stem from early decrements in cognitive ability in those with poor cardiovascular health that are already evident by midlife. Whether such associations are causal, however, or develop in tandem due to shared factors encountered earlier in life, remains unclear.MethodA modified version of the American Heart Association Life’s Essential 8 (LE8) cardiovascular health score was constructed in 8,226 participants (age 47 years) recruited to the 1970 British Cohort Study. Four biological (BMI, blood pressure, glucose, total cholesterol) and four behavioral (diet, physical activity, smoking, sleep) metrics were each categorized as 0 (poor), 1 (intermediate), or 2 (ideal) and summed to create the LE8 score. A cognitive test battery assessing immediate and delayed memory recall, executive function, processing speed, and overall cognitive function were chosen as outcomes. Multiple linear regressions employing multiple imputation and adjusting for a range of early (childhood socioeconomic status, household overcrowding, childhood IQ, and highest education level) and mid‐life (current socioeconomic status and malaise) factors were used to conduct analyses whilst accounting for missing data.ResultOverall cognitive function in those classed as having ideal (LE8>13 points) cardiovascular health was 0.15 (0.04–0.27) z‐scores higher than those with intermediate (LE8 9‐13 points) and 0.42 (0.30–0.55) z‐scores higher than those with poor (<9 points) cardiovascular health. In age‐ and sex‐adjusted analyses, each 1‐point increase in LE8 was associated with a 0.02–0.06 z‐score higher cognitive function in all domains (p<0.001 for all). These associations became null for executive function and processing speed once accounting for early‐life factors, however, and were substantially attenuated for both memory domains. Further adjustment for midlife factors had little further impact on estimates. Follow‐up analyses suggested stronger relationships between midlife cardiovascular health behaviors and cognitive ability than biological factors.ConclusionMuch of the observed relationship between cardiovascular health and cognitive ability in early midlife is likely explained by other shared early‐life factors. While a modest association still persists after accounting for these factors, the directionality of this relationship remains to be determined.
Understanding the Complexities of Caregiving for Alzheimer’s Disease and Related Dementias in Uganda: A Qualitative Insight
Authors: Onoria Joy 
Published: January 2025

AbstractBackgroundIn Uganda, caregivers of Alzheimer’s disease and related dementias (ADRD) face complex challenges, often lacking specialized skills for effective caregiving. Despite the growing prevalence of ADRD in the country, there’s a significant literature gap on caregiver selection and obstacles faced in urban and rural areas. This study aims to provide insights into the experiences of Ugandan caregivers, enhancing understanding of ADRD caregiving.MethodThis qualitative study involved 14 caregivers from Nansana and Busukuma, suburban areas of Wakiso District, Uganda. A purposive sampling strategy ensured representation across diverse age and sex groups. In‐depth interviews, each lasting to 60‐90 minutes, were conducted in Luganda to ensure cultural relevance. The interviews were meticulously transcribed verbatim, forming the basis of thematic analysis. This analysis involved a detailed coding process to compare and examine participants’ responses regarding uniformity, emerging patterns, and contradictions, thereby offering nuanced insights into the caregiving experience in ADRD.ResultThe study identified three primary themes within the caregiving experience for ADRD: relational foundations, multidimensional struggles, and the positive outcomes of caregiving. Caregiver selection is primarily influenced by existing family dynamics, with emotional bonds and patient preferences as crucial factors. Caregivers reported experiencing a spectrum of challenges, including emotional tolls, physical demands, and considerable financial sacrifices such as role reversals and the physical burden of care. Despite these challenges, many caregivers identified positive aspects, including enhanced empathy, acquisition of professional caregiving skills, and deepened sense of reciprocity. The thematic analysis provided a nuanced view of these complexities and benefits.ConclusionThis study offers vital insights into the experiences of caregivers of patients with ADRD in Uganda, highlighting the need for culturally sensitive support systems that integrate familial dynamics and caregiver experiences into healthcare policies. Recommendations include tailored training, community‐based networks, and digital platforms for remote support. Future research should broaden caregiver demographics and employ longitudinal studies. These findings are crucial for enhancing caregivers’ and patients’ quality of life, emphasizing the indispensable role of caregivers in ADRD management in Uganda and similar settings.
Regional and national heatmaps of dementia and mild cognitive impairment over time in Greece: Recent past and current status along with predictions for 2035 and 2050
Authors: Skolariki Konstantina , Exarchos Themis , Machairaki Vasiliki , Lyketsos Constantine G. , Vlamos Panagiotis , Scarmeas Nikolaos ,   Hellenic Initiative Against Alzheimer’s Disease (HIAAD)
Published: January 2025

AbstractBackgroundGreece has among the largest proportions of elderly worldwide and is among the fastest aging countries in Europe. Consequently, the population suffering from mild cognitive impairment (MCI) or dementia is one of the largest in Europe. This population varies significantly within the different regions in Greece.MethodWe estimated the number of patients living with MCI or dementia in Greece and created heatmaps, by prefecture, for 4 different census periods, 1991, 2001, 2011 and 2021 (due to COVID results for 2021 were obtained in 2023). The prevalence of MCI and dementia, for men and women of different age categories (65‐69, 70‐74, 75‐79, 80‐84, 85+) were obtained from the The Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Each prevalence for age and sex was multiplied by the respective number of people from the census, based on sex and age category.ResultThe analysis showed an increase in numbers in all prefectures, ranging for MCI from 177,898 in 1991, to 223,982 in 2001, 274,872 in 2011 and 311,189 in 2021 and for dementia from 103,535 in 1991, to 113,144 in 2001, 166,774 in 2011 and 206,939 for 2021. Projected estimates for the number of people with MCI or dementia with heatmaps were generated for 2035 and 2050, based on a Greek census projection estimating the number of people above 65 and above 85, for the above years. The projection indicates a great increase in number of persons with MCI to 375,000 in 2035 and 440,000 in 2050 and for dementia to 250,000 in 2035 and 310,000 in 2050.ConclusionConsidering the fact that each person requires care over time from at least 2 other caregivers, the above numbers demonstrate the impact that the dementia pandemic will have in Greece. These heatmaps can be used as a tool in policy making, aiming to organize the setup and development of memory clinics and day care centers in the different prefectures in Greece, where the need is higher based on the number of patients.
Racial/Ethnic Differences in Physical Activity Participation of Dementia Caregivers in the US: Findings from the 2017 BRFSS Survey
Authors: Liang Jiaming 
Published: January 2025

AbstractBackgroundIt is well documented that participating in physical activity can help dementia caregivers alleviate stress and enhance well‐being. However, few studies have examined dementia caregivers’ needs for exercise, and the feasibility of promoting their physical activity amidst heavy caregiving responsibilities. This study compared the participation of physical activity between dementia caregivers and non‐caregivers, and examined effects of racial/ethnic identities and other sociodemographic factors on dementia caregivers’ physical activity participation.MethodA cross‐sectional study was conducted using the 2017 Behavioral Risk Factor Surveillance System (BRFSS) Survey. Participants’ physical activity engagement was measured using four indicators: hours of (1) all physical activities, (2) moderate activities, and (3) vigorous activities in the last 30 days, and (4) whether meeting the WHO aerobic exercise recommendation. Regression and interaction analyses were used to examine associations between being dementia caregivers and physical activity participation, and factors related to physical activity status of dementia caregivers.ResultThe study included 10,158 participants (280 dementia caregivers and 9,878 non‐caregivers). Compared to non‐caregivers, dementia caregivers tend to be older (≥ 55‐year‐old, 67% vs. 55%), more likely to be women (63% vs. 51%), have a higher level of education (≥ Bachelor’s degree, 56% vs. 50%), and more likely to own houses (83% vs. 71%). Between‐group comparison found no difference between dementia caregivers and non‐caregivers on all four physical activity indicators. Regression analyses found that, Hispanic participants tend to report more hours of physical activity participation than non‐Hispanic Whites. However, interaction analyses revealed that Hispanic dementia caregivers have significantly fewer hours of participating in moderate physical activity (12.96±8.52 vs 23.20±1.10), and are less likely to meet the WHO aerobic recommendation (OR: 0.70±0.10 vs 0.83± 0.10) than Hispanic non‐caregivers. The analyses also found that dementia caregivers report fewer moderate activity hours if they are unemployed (15.71±5.92 vs. 23.44±0.99).ConclusionThe findings suggest that dementia caregiving does not necessarily reduce physical activity hours of caregivers, unless they are Hispanic and unemployed. Future intervention development should focus on promoting moderate and aerobic exercise participation among dementia caregivers, especially in developing culturally and linguistically appropriate programs for Hispanic dementia caregivers.
Longitudinal associations between self‐reported exercise levels and Alzheimer’s related biomarkers in Autosomal Dominant Alzheimer’s Disease
Authors: Sewell Kelsey R , Doecke James D. , Sohrabi Hamid R. , Rainey‐Smith Stephanie R , Peiffer Jeremiah J , Bateman Randall J. , Morris John C. , McDade Eric , Martins Ralph N , Brown Belinda M. ,   The DIAN Study Group
Published: January 2025

AbstractBackgroundAccumulating evidence indicates exercise may delay or prevent the onset of Alzheimer’s disease (AD). To our knowledge, no study has investigated the longitudinal impact of exercise on AD‐related biomarkers in individuals with Autosomal dominant Alzheimer’s disease (ADAD) mutations who are destined to develop AD. This study examined longitudinal associations between self‐reported exercise levels and AD‐related biomarkers in a cohort of ADAD mutation carriers and investigated whether observed associations depended upon disease stage.MethodThis prospective cohort study included participants from the Dominantly Inherited Alzheimer’s Network (DIAN). Participants were n = 308 ADAD mutation carriers aged 39.7 ± 10.8 years (56.5% female) with data available for self‐reported exercise participation and either brain imaging (hippocampal volume, total volume, gray matter volume, white matter hyperintensities, brain Aβ), or biomarkers quantified from cerebrospinal fluid (Aβ40, Aβ42, p‐tau, t‐tau, p‐tau/Aβ42, and Aβ42/40). Associations between exercise and AD biomarkers (i.e., from brain imaging and CSF) were examined using linear mixed models.ResultGreater weekly baseline exercise was associated with slower accumulation of brain Aβ at preclinical disease stages (β = ‐0.16, 95% CI ‐0.23 – ‐0.08), and slower decline of right and left hippocampal volume (β = 0.06, 95% CI 0.03–0.08; β = 0.06, 95% CI 0.02–0.09, respectively), total cortical volume (β = 0.03, 95% CI 0.01–0.05), total subcortical gray matter volume (β = 0.03, 95% CI 0.01–0.05), and total gray matter volume (β = 0.03, 95% CI 0.01–0.05), effects which became significant approximately 5 years before predicted cognitive symptom onset.ConclusionThese findings demonstrate that exercise is associated with more favourable profiles of AD‐related biomarkers in those with ADAD mutations. The causal direction of this research is difficult to ascertain, thus future study designs investigating the therapeutic potential of exercise in both ADAD and late‐onset AD should be considered before clinical recommendation of exercise is implemented.
Comparing the dynamics of multiple cognitive markers for Alzheimer’s disease progression using a novel double anchoring events‐based sigmoidal mixed model
Authors: Kang Kaidi , Zhang Panpan , Dumitrescu Logan C. , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo‐Eun , Scollard Phoebe , Gibbons Laura E. , Trittschuh Emily H. , Mez Jesse , Saykin Andrew J. , Buckley Rachel F. , Gao Xiaoting , Di Jianing , Crane Paul K. , Hohman Timothy J. , Liu Dandan 
Published: January 2025

AbstractBackgroundUnderstanding the dynamics of markers throughout Alzheimer’s disease (AD) progression in a representative population is critical for early detection of AD. Most existing studies used a single cohort to model the dynamics of AD‐related markers, which may lead to biased and unreproducible results. The Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP‐PHC) harmonized rich endophenotype data across multiple cohort studies, providing valuable resources for ADRD research. Using harmonized cognitive markers from ADSP‐PHC, we modeled and compared dynamics of memory, language, and executive function over AD progression through a novel double anchoring events‐based sigmoidal mixed model (DSMM).MethodThe study included diagnostically irreversible participants with clinical diagnoses of mild cognitive impairment (MCI) and/or AD (n = 5,475; Table 1). A novel DSMM used time to the first diagnosis of AD as time scale, and extended the standard sigmoidal mixed model to include the participants with unobserved AD diagnosis by jointly modeling the duration between the first diagnoses of MCI and AD. The model provided inference about initial score, maximum decline (of score) and half‐life of decline (time from when score dropped by half) for the population. A log‐linear model characterizing the duration between clinical diagnoses of MCI and AD was adjusted for age (at MCI diagnoses), sex, apolipoprotein E‐ε4 status, and their interactions.ResultThe three cognitive markers have similar initial scores (memory: 0.33, 95%CI: 0.08‐0.54; language: 0.29, 95%CI: 0.14‐0.41; executive function: 0.31; 95%CI: 0.18‐0.40). Memory has the largest decline (β = 1.45, 95%CI: 1.01‐1.90), followed by language (β = 1.33, 95%CI: 0.81‐1.82) and executive function (β = 1.20, 95%CI: 1.01‐1.39). The half‐life of decline is the shortest for memory (β = ‐0.69, 95%CI: ‐1.72‐0.34), followed by language (β = 0.08, 95%CI: ‐0.88‐1.01) and executive function (β = 0.26, 95%CI: ‐0.41‐0.94; Figure 1).ConclusionA novel DSMM was used to characterize the dynamics of multiple harmonized cognitive markers related to AD progression using multiple harmonized cohorts from ADSP‐PHC, empirically determining the temporal order of decline of harmonized cognitive markers: memory, then language, and lastly executive function. The study improved the representativeness of the research sample by using multiple cohorts and harmonized cognitive markers, and DSMM helped reduce selection bias by including participants without observed clinical diagnosis of AD.
Randomised Controlled Crossover Trial Evaluating Two Caregiver‐Delivered Music Listening Interventions for Community‐Dwelling People with Dementia
Authors: Hofbauer Lena M , Rodriguez Francisca S 
Published: January 2025

AbstractBackgroundGiven that the majority of people with dementia live in their homes in the community and are primarily cared for by informal caregivers, there is a growing interest in developing interventions suitable for this setting. Further, it is important to establish how music selections can differentially affect PwD. In this pilot trial, we thus compare two caregiver‐delivered music listening MBIs with care‐as‐usual.Methods17 PwD‐caregiver‐dyads were randomised to receive 6 weeks of ‘MBI A’ and ‘MBI B’, the order was crossed over. As control, half of the participants also underwent 6 weeks of care‐as‐usual. MBI A consisted of fast, positively valenced music while MBI B consisted of slow, positively valenced music. The music was provided on tablet or CD. Quantitative outcomes were cognition, well‐being, quality of life, and caregiver‐reported behavioural and psychiatric symptom severity and related distress. Outcomes were analysed in separate mixed‐effect models adjusted for baseline values, period, and intervention adherence. Dyads’ descriptions of experiences were narratively summarised.ResultsMusic listening was associated with an initial increase in quality of life. Further, MBI A was associated with superior delayed recall compared to MBI B (MBI A‐B: 1.04 [95% CI: 0.16, 1.92], Hedge’s gav = 0.70). Dyads’ descriptions highlight differential positive effects of MBI A and B ‘in‐the‐moment’ of listening. Positive effects of MBI A included heightened mood and movement, MBI B was associated with relaxation. Dyads suggested that future iterations of the MBI may (i) be usable by PwD on their own, (ii) contain longer playlists, and (iii) be individualised.ConclusionOverall, the music listening intervention created value for PwD, increasing quality of life and inducing positive experiences ‘in‐the‐moment’. The recall‐enhancing effect of listening to fast, positively valenced music over a prolonged period should be investigated further and may be relevant to targeted uses of music with PwD. While the MBI design used in the present investigation can be described as feasible overall, adapting it so that PwD may use the intervention independently may be a valuable next step.
Neighborhood social cohesion, racial composition, and walkability and dementia risk: The Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study
Authors: Besser Lilah M , Zanwar Preeti Pushpalata , Meyer Oanh L. , Sohn Elisabeth K. , Yen Irene H. , Kandula Namratha R. , Kanaya Alka M. 
Published: January 2025

AbstractBackgroundPrior studies suggest that neighborhood socioeconomic status, neighborhood walkability, and neighborhood social cohesion are associated with cognitive function and dementia risk. However, little is known about how neighborhood social and built environments influence dementia risk in South Asian populations residing in the US.MethodsWe used data from 745 South Asian individuals ≥40 years in the US who completed Exam 2 (2015‐2018) of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. Neighborhood characteristics at Exam 1 (2010‐2013) included neighborhood percentage of Asian residents (range: 0‐87%), neighborhood Walk Score (i.e., walkability) (range: 0‐100), and neighborhood social cohesion (range: 5‐25). We calculated a modified Washington Heights/Inwood Columbia Aging Project (WHICAP) dementia risk score (range: 0‐52) for Exam 2 based on age, gender, education, diabetes, hypertension, current smoking status, low high‐density lipoprotein, and high waist‐to‐hip ratio. Multivariable linear regression examined associations between neighborhood characteristics and the dementia risk score, controlling for age (in years), marital/partner status, family income, study site, years residing in the neighborhood at Exam 1, neighborhood socioeconomic status, and percentage of life lived in the US. Interaction terms tested whether associations differed by gender.ResultsOur sample was comprised of 45% women, 90% achieved a bachelor’s degree, and 84% were born in India, while the remainder originating from Pakistan, Sri Lanka, Sub‐Saharan Africa, the US, and other countries. Mean age was 59 years old (SD = 9). The mean dementia risk score was 8.4 for women (SD = 5.3) and 10.0 for men (SD = 4.8) (overall sample range: 0‐31). In multivariable analyses, greater neighborhood social cohesion at Exam 1 was associated with lower dementia risk scores at Exam 2 (estimate: ‐0.15, 95% CI: ‐0.28, ‐0.03). In stratified analysis, greater neighborhood social cohesion was associated with lower dementia risk scores for women (estimate: ‐0.28, 95% CI: ‐0.46, ‐0.10) but not men (estimate: 0.02, 95% CI: ‐0.15, 0.19) (interaction p‐value: 0.01). No associations were observed between neighborhood walkability or neighborhood percentage of Asian residents and dementia risk score.ConclusionNeighborhood social cohesion may help reduce the risk of dementia among South Asian middle to older‐age women in the US.