bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unleashing the power of a willow bark‐derived tannin to alleviate behavioral deficits in a preclinical model of Alzheimer’s disease
Authors: Kahil Ezaldean A , Jackson Anisha , Patel Kruti , Coward Lori A , D'Souza Bernadette , Gorman Gregory , Jumbo‐Lucioni Patricia 
Published: January 2025

AbstractBackgroundDespite some advances in treatment, a cure for Alzheimer’s disease (AD) remains elusive. Disease hallmarks include heightened neuroinflammation and oxidative stress, associated with progressive decline in mobility and cognitive functions. Natural compounds provide a valuable reservoir of novel bioactive substances with therapeutic potential, fewer side effects, and increased affordability. The plant‐derived tannin 1,2,3,4,6‐Penta‐O‐Galloyl‐β‐D‐Glucose (β‐PGG) displays potent antioxidant, anti‐inflammatory, and neuroprotective properties in vitro, but in vivo evidence is limited. This study assesses the dose‐dependent efficacy and therapeutic mechanisms of β‐PGG in mitigating age‐dependent mobility deficits in a Drosophila melanogaster model of AD.MethodA fruit fly line overexpressing the human amyloid precursor protein (hAPP) and β‐site APP‐cleaving enzyme (hBACE), in neurons was used as AD model. Newly eclosed flies were supplemented with 0, 5, or 10µM β‐PGG and locomotion was assessed at 7, 14, 21, and 30 days via a negative geotaxis assay. The number of flies passing 2‐, 4‐, and 8 cm marks in 10 seconds was recorded by genotype, sex, age, and treatment. Oxidative stress sensitivity was measured by quantifying 48‐hour survival to paraquat exposure. Flies were homogenized to determine levels of β‐PGG metabolites by LC/MS/MS. Data were analyzed via a two‐way ANOVA to test the effects of genotype, treatment and their interaction in young (7‐ and 14‐days old) and old (21‐ and 30 days old) flies.ResultYoung non‐supplemented AD females (p<0.0001) and males (p<0.0001) moved significantly slower than controls. β‐PGG significantly ameliorated locomotion deficits in young AD flies. AD females (p<0.0001) and AD males (p<0.0001) supplemented with 10µM β‐PGG were significantly less movement impaired than their non‐treated counterparts. Regardless of genotype, old females supplemented with 10µM β‐PGG were significantly faster than untreated cohorts (p<0.05). Conversely, old AD but not control males supplemented with 10µM β‐PGG were significantly less movement impaired than their untreated counterparts (p<0.0001). At 48 hours, 2‐week β‐PGG supplementation significantly improved survival to paraquat among control females but not in males (p<0.01).ConclusionOur findings provide strong evidence that β‐PGG supplementation mitigates age‐associated mobility deficits in our preclinical model of AD. Benefits from this supplementation may delay physiological aging in a sex‐specific manner.
Genetic and Sex Associations with Earlier Estimated Onset of Amyloid Positivity from over 4000 Harmonized Positron Emission Tomography Images
Authors: Castellano Tonnar , Wang Ting Chen , Nolan Emma , Archer Derek B. , Cody Karly , Harrison Theresa M. , Wu Yiyang , Durant Alaina , Janve Vaibhav A , Engelman Corinne D. , Jagust William J. , Albert Marilyn S. , Johnson Sterling C. , Resnick Susan M. , Sperling Reisa A , Bilgel Murat , Saykin Andrew J. , Vardarajan Badri N , Mayeux Richard , Betthauser Tobey J. , Dumitrescu Logan C. , Mormino Elizabeth , Hohman Timothy J. , Koran Mary Ellen I. 
Published: January 2025

AbstractBackgroundNew techniques have been developed to estimate the age when someone converted to amyloid positivity (EAOA) from PET, oftentimes offering information Aβout a participant decades before they joined a research study. EAOA is variable across populations but we do not know the causes for these differences. This study aims to validate APOE associations with EAOA and explore genetic and sex‐based factors with EAOA.MethodsData from six cohorts were analyzed. Our analysis included 4220 non‐Hispanic white people (57.6% women; 86.7% cognitively unimpaired at baseline scan). Amyloid PET data were harmonized using gaussian mixture models. EAOA was calculated using the sampled iterative local approximation (SILA) algorithm. Sex differences in EAOA were compared using t‐tests amongst amyloid positive individuals. A genome‐wide association study of EAOA was performed. Gene analyses were conducted using MAGMA.ResultsAverage EAOA was 81.1 years across all individuals regardless of amyloid status. APOE e2 homozygotes had slightly later EAOA than e3/e3 homozygotes. APOE e4 homozygotes converted to amyloid positivity 8.2 years before e3/e4 heterozygotes and over two decades earlier than e3 homozygotes. APOE e2/e4 converted to positivity roughly three years later than e3/e4 and nearly ten years earlier than e3 homozygotes. APOE genotype differences in EAOA described were statistically significant (p < .01). There were significant sex differences between men and women when examining amyloid positivity. Men converted to amyloid positivity over 2 years later than women (65.3 vs 63.2 years, p=3.23x10‐5). The rs12981369 polymorphism in ABCA7 was associated with EAOA (β = 2.14, p=9.27×10−9). Brain eQTL databases indicate associations between rs12981369 and gene expression of ABCA7. Gene‐level analyses revealed significant associations for ABCA7, HMHA1, and KIF13B.ConclusionThis study further describes the role of APOE and reveals roles for ABCA7 and KIF13B on amyloid onset. We identified a novel variant on chromosome 19 correlating with later amyloid onset conversion and highlight important differences between sexes. These findings highlight EAOA as a powerful endophenotype of AD and offer insights into potential drug‐targetable mechanisms for early AD intervention.
Luteolin and curcumin in rodent models of cognitive disorders: a dose‐response perspective
Authors: Führ Giulia A , Zimmer Aline R. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. Although AD is characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), it’s estimated that nearly half of AD cases might be attributed to modifiable risk factors and lifestyle‐based interventions may offer promising preventative strategies to delay disease onset and progression. Polyphenolic derivatives easily found in foods like luteolin and curcumin have shown beneficial effects to counteract cognitive decline.MethodA systematic review was conducted to determine the oral therapeutic doses of curcumin and luteolin used in experimental models of cognitive disorders in rodents, presenting beneficial effects. Public databases, including PubMed, Embase, Web of Science and Scopus were searched. Original research and review papers published between 2009 and 2023 using the following keywords: “luteolin,” “curcumin,” “oral administration,” “cognitive disorder,” “mice,” and “rats” were included in the search.ResultEleven articles for luteolin and twenty‐seven for curcumin fit the inclusion criteria. For luteolin, the oral doses range from 1.25 mg/kg to 200 mg/kg, with treatment length from 7 days to 5 months. For curcumin, oral doses range from 0.4 mg/kg to 400 mg/kg, with treatment length from 2 days to 6 months. The studies demonstrated that luteolin reduces the deposition of Aβ, oxidative stress, neuroinflammation, neuronal damage and neuronal insulin resistance, improving learning and memory and rescuing cognitive impairment. Curcumin reduces oxidative stress and Aβ production and promotes hippocampal neurogenesis, improving spatial learning, memory and cognitive function. None of the studies evaluated reported toxic effects at the tested doses. The use of both compounds in combination was not found in the literature. The most promising doses for improving cognitive function in experimental models ranging 10 – 20 mg/kg for luteolin and 25 – 50 mg/kg for curcumin.ConclusionLuteolin and curcumin exhibit multi‐target pharmacological properties, suggesting the potential to prevent cognitive disorders, including AD. The neuroprotective effect of these agents in combination and whether this would lead to a dose reduction and an improvement in effect is still a subject to be explored.
Single nucleotide polimorphisms of the main glutamate transporter in the brain are associated with lower regional brain glucose metabolism in cognitively impaired individuals
Authors: de Oliveira Roberta dos Santos , Limberger Christian , Machado Luiza Santos , de Bastiani Marco Antônio , Schlickmann Thomas Hugentobler , Carello‐Collar Giovanna , Povala Guilherme , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundAstrocytes play a main role in brain energy metabolism, primarily through the metabolic cooperation with neurons. The use of [18F]fluorodeoxyglucose(FDG)‐PET has become a valuable indicator of neurodegeneration in Alzheimer's disease (AD), revealing a brain hypometabolic signature, but it is sensitive to changes in astrocyte metabolism. It is postulated that the activation of the excitatory amino acid transporter 2 (EAAT2) is the main trigger of FDG‐PET uptake in astrocytes. However, the potential relationship between single nucleotide polymorphisms (SNPs) in the gene that encodes for EAAT2 (SLC1A2) and the AD hypometabolic signature remains unknown. Here, we investigated whether SNPs in SLC1A2 affect brain glucose metabolism in cognitively impaired (CI) individuals.MethodWe assessed 331 CI individuals from the ADNI cohort with available [18F]FDG‐PET imaging data, CSF Aβ1‐42 and p‐tau181 measures, and genotyping data of SLC1A2 (Table 1). After the genetic data processing, 100 SNPs from the SLC1A2 gene were identified. In this study, we focused on the 10 SNPs more associated with [18F]FDG SUVR in an exploratory ROI‐wise analysis. Then, we performed voxel‐wise correlation analysis with RMINC, testing the association between the SLC1A2 SNP carriership and [18F]FDG‐PET, adjusting for age, sex, APOE4 status, and CSF Aβ42 and p‐tau181 levels (corrected p‐value < 0.05).ResultOur findings revealed a negative association between four SLC1A2 SNPs and [18F]FDG‐PET in specific brain regions. This indicates that SLC1A2 SNP carriership is associated with lower regional glucose metabolism. Notably, rs57339940 carriers presented a significant cluster in the cingulate region (tmax = 3.04, p < 0.01, Figure 1A). Carriers of rs11033098 and rs11033099 exhibited bilateral clusters in areas of the lingual gyrus (tmax = 2.4806 and tmax = 2.8736, respectively, p < 0.01, Figure 1B‐C). Additionally, individuals with rs10768132 showed a substantial bilateral impact on the posterior areas of the cuneus (tmax = 2.9821, p < 0.01, Figure 1D).ConclusionThese preliminary results show that SLC1A2 SNP carriership had a significant influence on regional glucose hypometabolism, specifically in areas comprising the occipital lobe and the cingulate region. Metabolic alterations may influence the susceptibility of those regions to accumulate amyloid in later stages of AD.
Sex‐specific relationships among risk factors in those with Mild Cognitive Impairment or Alzheimer’s disease and healthy controls
Authors: Intzandt Brittany , Ramirez Joel , Lam Benjamin , Masellis Mario , Scott Christopher J. M. , Einstein Gillian , Bherer Louis , Black Sandra E ,   ONDRI Researchers; CCNA Researchers
Published: January 2025

AbstractBackgroundDementia incidence is projected to significantly increase, posing unique challenges to healthcare systems. Identifying non‐modifiable and modifiable risk factors (RF) is crucial, including sex‐specific factors, given the higher prevalence among females (60%). Here, we employed a network analysis to examine prominent RF in healthy controls compared to those with cognitive decline (CD), as well as the interrelationships and interactions of RF on CD. Additionally, sex‐specific networks were compared to identify unique RF and interactions present among sex.MethodHealthy controls and CD individuals (mild cognitive impairment and Alzheimer’s dementia) were included from the Ontario Neurodegenerative Initiative and Canadian Consortium for Neurodegeneration in Aging (n = 339 total; 52% female; 72% CD). Non modifiable RF (e.g., age), modifiable RF (e.g., Framingham RF) and cognitive outcomes (e.g., executive functioning) were included in network modeling. Sex‐specific networks were created within the CD group and compared, as was between CD and healthy controls. Relationships among RF present in CD were identified and the strength. Nodes represented RF and edges are the pairwise dependency between RF, node centrality was investigated for the relative importance of each RF in the network.ResultHealthy controls and CD had statistically different networks (M = 0.536; p = 0.02), and the CD network had greater connectivity (S = 2.69; p = 0.005)[Figure 1]. Male and female networks were statistically different within CD (M = 0.432; p = 0.027), and the male’s network had statistically greater connectivity than the females with CD (S = 1.24; p = 0.049)[Figure 2]. Within females, the CD had significantly greater connectivity (S = 0.90; p = 0.03)[Figure 3] than healthy controls and no difference in males (p > 0.05).ConclusionOur findings reveal unique sex‐specific network patterns of RF for CD, which further underscores the need for sex‐disaggregated analyses. The observed differences in heightened connectivity of typically studied RF in males, highlights a potential gap in the understanding of sex‐specific RF for Alzheimer’s. Future work should incorporate biomarkers, such as neuroimaging, to further comprehend sex‐specific RF for CD and to create the framework for precision medicine in targeting sex‐specific RF for CD.
The World‐Wide FINGERS Global Strategy for Precision Prevention of Dementia and Alzheimer’s Disease
Authors: Mangialasche Francesca , Matton Anna , Ngandu Tiia , Lehtisalo Jenni , Udeh‐Momoh Chi , Alanko Vilma , Barbera Mariagnese , de Jager Celeste A , Peltonen Markku , Perera Dinithi , Stephen Ruth , Solomon Alina , Kivipelto Miia ,   World‐Wide FINGERS network
Published: January 2025

AbstractBackgroundPrecision Prevention –the right intervention for the right person at the right time– is a recent endeavour in the Alzheimer’s disease (AD) field, requiring the integration of multidimensional data from large, representative populations, to identify phenotypes for early and accurate detection of prevention potential.AimsThe World‐Wide FINGERS (WW‐FINGERS) network of multidomain trials for risk reduction and prevention of dementia includes 60+ countries. The network aims to adapt and test the original model from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which showed that a multidomain intervention can benefit cognition in older adults at‐risk of dementia. WW‐FINGERS works towards trials data harmonization, to enable joint data analysis.MethodsInternational Working Groups (IWGs) focused on trials´ prominent features were established to leverage the WW‐FINGERS expertise, facilitate data harmonization and joint analysis. Mapping and harmonization of data across the trials is ongoing, via periodic meetings and RedCap‐supported digital surveys done within the network.ResultsThe WW‐FINGERS network completed 14 trials, while 21 are ongoing, accounting for 18000+ participants. Trial Harmonization Guidelines were compiled, to support prospective data harmonization. Two IWGs –Cognitive Outcomes and Biorepository/Biomarkers– conducted surveys to map the current data and sample collection within the network. The Cognitive Outcome survey included data from 25 studies, showing target population ‐from asymptomatic at‐risk of dementia to early symptomatic stages‐, ethnicities within the trials (including 20% Caucasian, 10% Asian, 8% Black African, 7.5% mixed ethnicity, 4% Hispanic/Latino, 5% Caribbean), use of cognitive tests in 19 languages, with composite neuropsychological test batteries being most frequently used, capturing memory, executive function, and processing speed. The Biorepository/Biomarker survey was completed for 29 trials, including information on sample types, processing, storage, APOE availability and other biomarkers. Survey results are informing data harmonization and protocols for new trials. Additional IWGs are planned, including Neuroimaging, Non‐Cognitive outcomes and Health‐economics. Collaborations with international stakeholders are ongoing to maximize outreach and enable data sharing.ConclusionThe WW‐FINGERS global collaboration is enabling scalability and evolution of the FINGER model, and prospective harmonization of multidomain trials, establishing the base for a Precision Prevention approach in AD and dementia.
Impacts of Informant Replacement in Industry‐Sponsored Alzheimer’s Disease Clinical Trials
Authors: Nishida Mikaela K , Nuño Michelle M , Grill Joshua D , Gillen Daniel L 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD) clinical trials, participants must enroll with a study partner informant who accompanies them to visits and completes validated instruments. Mid‐trial informant replacement (IR) has been found to impact academic trial results. We hypothesized that a similar impact would be observed in industry‐sponsored trials.MethodWe conducted a retrospective analysis of two industry‐sponsored AD clinical trials testing semagacestat in mild‐to‐moderate AD. We assessed the relationship between IR and Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) score between visits using generalized estimating equations (GEE). The outcomes of interest were mean change in ADCS‐ADL between successive visits and the mean absolute change in ADCS‐ADL between successive visits, which was used to assess variability. Both models were adjusted for a priori‐specified potential confounding variables including participant sex, age, informant type, trial, time, and previous ADCS‐ADL measurement. To analyze impacts on a primary outcome measure, we used an ANCOVA model to estimate the association between IR and 76‐week change from baseline in ADCS‐ADL, where we adjusted for participant sex, age, informant type, trial, and baseline ADCS‐ADL measurement. We conducted an F‐test to compare the variances of this change.ResultAmong N = 2642 randomized participants, 72 (∼3%) of participants experienced IR at least once with a total of 81 occurrences. For visits standardized to be three months apart, we estimated that the difference in the mean between‐visit change in ADCS‐ADL was approximately ‐1.41 points (95% CI: ‐3.52, 0.72; P = 0.194) and the difference in the mean between‐visit absolute change was approximately 1.85 points (95% CI: 0.22, 3.49; P = 0.026), comparing participants who experienced IR to similar participants who had stable informants. We did not estimate a statistically significant difference in week‐76 change from baseline ADCS‐ADL (Est. = ‐0.98, 95% CI: ‐6.02, 4.06; P = 0.702) or a significant ratio of variances (Est. = 1.09, 95% CI: 0.65, 2.17; P = 0.700) comparing this measure for participants with IR to those with stable informants.ConclusionIR is associated with increased variability in ADCS‐ADL measurements between successive visits and should be considered when planning AD clinical trials.
Perceived threat of Alzheimer’s disease and dementia predicting health behavior
Authors: Dhaliwal Ravneet K. , Jacova Claudia , Marx Hannah , Robertson Frank , Gehling Jacklyn 
Published: January 2025

AbstractBackgroundFactors influencing health behaviors among older adults experiencing cognitive changes are important to understand in order to successfully promote preventative public health programs for Alzheimer’s disease and related dementias (ADRD). The Health Belief Model (HBM) has been utilized to investigate and predict health behaviors based on an individuals’ perceptions and beliefs. The aim of our study was to investigate the contribution of perceived threat (risk and worry) to individuals seeking care for cognitive changes.MethodParticipants of this study were 279 adults (M age = 73.8, range 60‐96; 54% female, 89% white, M education (years) = 14.9) recruited from the community, without neurocognitive diagnoses, and residing in the United States. They completed an online survey through Qualtrics. Participants rated their risk for developing ADRD and their worry about developing ADRD on 5‐point scales (risk: 1 = much lower than average to 5 = much higher than average; worry: 1 = not at all worried to 5 = very worried). They also answered questions about whether they noticed difficulties with their memory and cognition (yes/no), and whether they had seen a doctor for these changes (yes/no).ResultFollowing the HBM, perceived threat is separated into two variables: perceived susceptibility (risk) averaged M = 2.48 (58.4% rating in the 3‐5 range) and perceived severity (worry) averaged M = 2.05 (25.8% rating in the 3‐5 range). There were 101 participants (36%) who endorsed perceiving difficulties with their memory or cognition. Of these, only 3 participants (M age = 70.3, range 70‐71; 2 females, M education (years) = 14.7) said ‘yes’ to seeing their doctor about memory or cognitive difficulties (3%), preempting further predictive analyses.ConclusionWe found that despite endorsing memory/cognitive difficulties, and reporting above average risk and worry about ADRD, an exceedingly small number of adults aged ≥60 had consulted their doctor. Our findings align with previous research reporting that medical help‐seeking does not keep apace with perceived susceptibility to ADRD and worry in older adults. As a result, our understanding of factors that influence health behaviors, such as seeking care early on, remains limited.