bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease
Authors: Vattathil Selina M. , Bennett David A. , Schneider Julie A. , Wingo Aliza P. , Wingo Thomas S. 
Published: January 2025

AbstractBackgroundmicroRNAs (miRNAs) are small RNAs involved in regulating gene expression by repressing target protein‐coding genes. Hundreds of miRNAs are expressed in human brain, but our understanding of their role in Alzheimer’s disease (AD) and cognitive decline is limited.MethodWe performed miRNA differential expression analysis using small RNA sequencing data generated from dorsolateral prefrontal cortex samples from 641 participants of the Religious Orders Study (ROS) and Memory and Aging Project (MAP). After quality control, 528 miRNAs were available to test for differential expression in cognitive trajectory (for five cognitive subdomains and global cognition), amyloid, tangles, and AD clinical diagnosis. Initial analyses were performed using association models that included adjustment for technical and demographic covariates. To identify miRNAs associated with AD‐related outcomes independently of co‐occurring age‐related cerebral pathologies, secondary analyses were conducted using models augmented to also adjust for the pathologies. Sex interaction analyses were performed to identify sex‐biased miRNAs, and Mendelian randomization was conducted to assess the evidence that genetically‐regulated miRNA abundance mediates the observed trait associations.ResultWe identified 311 differentially expressed miRNAs for AD, its hallmark pathologies, or cognitive trajectory. Our secondary analysis identified 137 miRNAs that were associated with AD‐related outcomes independently of up to ten age‐related cerebral pathologies. The protein‐coding genes predicted to be repressed by the differentially expressed miRNAs were enriched in lipoproteins, transcription, postsynaptic signaling, and cellular senescence. Sex interaction analysis identified 5 miRNAs with different observed associations in males and females. Finally, Mendelian randomization identified 15 miRNAs with evidence that their expression roles play a causal role in the associated trait.ConclusionWe find evidence for some miRNAs being associated with AD‐related traits and cognitive trajectory through age‐related cerebral pathologies while other miRNAs are independently associated with AD‐related outcomes. The miRNAs consistent with a causal role are promising candidates for future studies in model systems to understand how miRNAs contribute to AD and cognitive decline.
Alzheimer’s disease‐associated gut microbes shape neuroinflammatory tone and disease outcomes in mouse models
Authors: Blackmer‐Raynolds Lisa , Sampson Maureen , Hamilton Adam M , Yang Aimee , Kozlov Anna , Lipson Lyndsey , Chang Jianjun , Kelly Sean D , Sloan Steven A , Sampson Timothy R. 
Published: January 2025

AbstractBackgroundChanges in neuroinflammatory tone have been shown to modulate neuroimmune responses to Alzheimer’s disease (AD) pathology and shape disease outcomes, however, extrinsic factors that modify neuroimmune activation remain poorly understood. The gut microbiome is one such factor, with the ability to shape peripheral and central immune activation, as well as AD pathologies. AD patients display unique changes in microbiome composition, however, the link between specific AD‐associated gut bacteria, neuroinflammatory tone, and AD outcomes remains to be elucidated.MethodTo identify AD‐associated bacteria that modify neuroinflammatory tone, wildtype germ‐free mice were mono‐colonized with type strains of bacteria species of interest (Escherichia coli, Bacteroides thetaiotaomicron, Clostridium celatum, and Lactobacillus johnsonii) for 2 weeks. Further evaluation of the effect of E. coli—an identified neuroimmune modulatory bacteria—on AD outcomes was performed by exposing conventional 5xFAD mice to E. coli via oral gavage for one month. Neuroinflammatory outcomes were assessed by bulk and single cell RNA‐seq and protein analysis. In addition, AD outcomes including cognitive and pathological markers were evaluated in E. coli exposed 5xFAD mice.ResultAD‐associated bacteria induced bacteria‐ and sex‐specific changes in cytokine levels as well as myeloid cell gene expression within the brains of mono‐colonized mice. In particular, E. coli was shown to induce a distinct, AD‐associated neuroinflammatory phenotype that was characterized by increased MHC II antigen presentation and changes in boarder associated macrophage and endothelial cell gene expression. Further, E. coli‐exposed 5xFAD mice displayed accelerated cognitive decline compared to vehicle controls. Neuroinflammatory and pathological markers in the brains of E. coli‐exposed 5xFAD mice were also evaluated to further explore the effects of E. coli on AD pathophysiology.ConclusionTogether, these results highlight the neuroimmune modulatory potential of AD‐associated gut bacteria. In particular, the present study demonstrates how increased intestinal exposure to non‐pathogenic E. coli is sufficient to modify neuroinflammatory tone, cognition, and pathology in 5xFAD mice, highlighting the potential importance of this microbe for AD.
Dyadic patterns of subjective cognitive decline and longitudinal cognitive outcomes
Authors: Houston Michelle L. , Zhang Panpan , Liu Dandan , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A. 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) may provide an early indicator of Alzheimer’s disease. Dyadic SCD, the self/patient’s in relation to an informant/loved one’s endorsement of SCD, may better reflect underlying Alzheimer’s pathology. We related dyadic SCD discrepancies to longitudinal changes of cognitive aging.MethodsVanderbilt Memory and Aging Project participants (cognitively unimpaired 71%, n = 537, 69.3±10.1 years, mean follow‐up time 5.9±2.8 years) and their informants completed the Everyday Cognition (ECog) questionnaire and Cognitive Complaint Questionnaire (CCQ). Dyadic discrepancy (self‐reported score minus informant‐reported score) was calculated and split into 3 levels (i.e., self>informant, informant>self, and dyadic concordance). Participants completed a diagnostic interview, neuropsychological testing, and multimodal brain MRI at each timepoint. Linear mixed‐effects regression models related baseline dyadic category to diagnostic conversion and longitudinal neuropsychological and neuroimaging outcomes. Models were adjusted for age, sex, self‐reported race/ethnicity, baseline diagnosis, APOE‐ε4 status, depression symptoms (Geriatric Depression Scale), and follow‐up time. A false discovery rate (FDR) correction for multiple comparisons was applied.ResultsDyadic discrepancy on the ECog did not relate to diagnostic conversion. Compared to dyadic concordance, individuals with greater self‐SCD on the CCQ related to diagnostic conversion (β = 2.96, p = 0.04). In secondary models stratified by diagnosis, cognitively unimpaired participants with greater self‐SCD were more likely to diagnostically convert (β = 6.48, p = 0.02). Compared to dyadic concordance, individuals with greater informant‐SCD on the ECog were associated with worsening executive functioning (β = ‐0.06, pFDR = 0.02), Boston Naming Test (BNT) (β = ‐0.42, pFDR<.001), and animal naming (β = ‐0.44, pFDR = 0.01). Compared to dyadic concordance, individuals with greater informant‐SCD on the CCQ were associated with worsening executive functioning (β = ‐0.08, pFDR = 0.01), memory (β = ‐0.07, pFDR = 0.01), and BNT (β = ‐0.53, pFDR<.001), with stronger associations in the mild cognitive impairment subgroup. Neither ECog nor CCQ dyadic discrepancy related to neuroimaging markers (pFDR>0.10).ConclusionsThe direction of dyadic discrepancy related differently to diagnostic conversion and cognitive performance. Greater self‐reported SCD related to greater likelihood of diagnostic conversion in cognitively unimpaired participants. However, greater informant‐reported SCD related to worsening cognitive performance. Results highlight that dyadic patterns of SCD differentially predict prognosis and incorporation of an informant provides important information. Further analyses will examine dyadic discrepancy and longitudinal biomarker patterns.
Loss of Alzheimer’s disease risk factor BIN1 from inhibitory neurons induces network hyperexcitability
Authors: Voskobiynyk Yuliya , Cochran J. Nicholas , Davis M. Natalie , Carullo Nancy VN , Day Jeremy J , Roberson Erik D 
Published: January 2025

AbstractBackgroundGenome‐wide association studies have identified genetic risk factors for AD, including a single nucleotide polymorphism in the bridging integrator 1 (BIN1) gene that is present in approximately 40% of the population and has the largest effect size of the common AD genetic risk factors. While the association between BIN1 and AD has been established, the mechanisms by which BIN1 contributes to AD remain understudied. We previously showed that increasing BIN1 expression in primary hippocampal neurons increases neuronal excitability (Voskobiynyk & Roth et al., 2020). However, expression of the primary neuronal isoform of BIN1 is reduced in AD patients compared to healthy age‐matched controls. We thus set out to explore the mechanism of BIN1’s contribution to network hyperexcitability in vivo.MethodsWe used conditional knockout mice to selectively reduce murine Bin1 from all neurons (Nestin‐Cre‐driven), excitatory neurons (CaMKIIα‐Cre‐driven), and inhibitory neurons (Viaat‐Cre‐driven). We then examined network hyperexcitability through a pentylenetetrazole‐induced seizure susceptibility assay; transcriptomic effects through bulk RNA sequencing, and behavioral effects through a battery of tests.ResultsPan‐neuronal loss of Bin1 increased seizure susceptibility in a gene‐dose‐dependent manner. Bin1 loss from excitatory neurons decreased seizure susceptibility, while Bin1 loss from inhibitory neurons increased seizure susceptibility. Bin1 loss from inhibitory neurons induced learning deficits and increased mortality of adult mice.ConclusionBin1 loss from inhibitory neurons led to increased seizure susceptibility, similar to the pan‐neuronal loss of Bin1, suggesting that loss of Bin1 from inhibitory neurons drives the effect of global loss of Bin1. Overall, this study contributes to our understanding of how BIN1 regulates network hyperexcitability at a cell‐type‐specific level.
Agreement between self‐ and informant‐reports of cognitive complaints in predicting time to an objective cognitive worsening in Cognitively Unimpaired (CU) and with Subjective Cognitive Decline (SCD) participants: Results from the CompAS longitudinal study
Authors: Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Lojo‐Seoane Cristina , Spuch Carlos , Aldrey Jose M. , Juncos‐Rabadán Onésimo , Rozas Arturo X. Pereiro 
Published: January 2025

AbstractBackgroundThe importance of coincidence of cognitive complaints between participants without objective impairment and their informants in predicting progression remains unclear (Nosheny et al, 2022). Our objective was to determine whether agreement in dyadic reporting at baseline can predict survival time to progression to MCI or dementia.MethodA sample of 145 participants from the CompAS Study was included in a survival analysis. They were identified at baseline as CU (N = 115) and SCD (N = 30) and re‐diagnosed as CU, SCD, MCI, or dementia from 17 to 76 months of follow‐up. ‘Agreement’ in the presence of complaints was computed depending on the informant and participant QAM scores (range: 7‐35) at baseline were above or below a cut‐off point (i.e., 10‐11): 1) Overreport by participant (i.e., QAM scores above the established cut‐off for participant and below for informant); 2) Agreement in presence of complaints (i.e., QAM total scores of both coincide in being above the established cut‐off point). The other two categories (i.e., Overreport by informant; Agreement in absence of complaints) were discarded because there were almost no cases. We performed a Cox proportional hazards regression model (no cases censored). The event was defined as stability when the baseline diagnosis remained stable over the follow‐ups and worsening when a change to MCI or dementia. ‘Agreement’ was introduced as a covariate. Two groups (CU; SCD) identified at baseline entered the model as strata.ResultThe model was statistically significant [model fit: ‐2 Log Likelihood = 1029.810, χ2 = 9.721, df = 1, p<.002]. ‘Agreement’ significantly predicts time survival [β = ‐.471, SE = .161, Wald = 8.569, p < .003] and HR = .575 (95% CI = .404‐.817) indicated that the risk of worsening per month was 42.5% (1‐.575 = .425) smaller for the ‘Agreement in presence of complaints’ than for the ‘Overreport by participant’ in both CU and SCD groups (Figures 1 and 2).ConclusionOur results suggest that compared to the ‘Overreport by participant’, the dyadic agreement in the presence of complaints decreases the risk of worsening over time. These results could have to do either with a greater awareness of one’s own difficulties or with the beneficial effect of agreeing on its detection with informants in pre‐symptomatic stages.
Microglial expression of Alzheimer’s risk factor BIN1 regulates tau pathology in PS19 mice
Authors: Sudwarts Ari , Hansen Mitchell , Wang Shuai , Smirnou Stanislau , Skorobovenko Vlada , Delozier Michaela , Thinakaran Gopal 
Published: January 2025

AbstractBackgroundMicroglia play significant roles in Alzheimer’s disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally‐characterised phenotypes uncovered from transgenic pathologies alone. BIN1 ‐ the second‐most significant risk gene for the development of late‐onset AD (LOAD) ‐ is expressed at high levels in neurons, oligodendrocytes and microglia. We examined microglial BIN1 expression and function and previously demonstrated that BIN1 regulates proinflammatory and disease‐associated activation responses in microglia in vitro and in vivo (PMID 35526014). However it’s role in AD‐specific pathologies is as yet unknown.MethodWe used a reverse‐genetic approach to conditionally delete Bin1 in microglia of the PS19 mouse model of tauopathy. We used histology, biochemistry and RNAseq analyses to determine the effects of Bin1‐cKO on tau pathology and microglial responses.ResultOur data demonstrate that microglial BIN1 facilitates levels of pathologically phosphorylated tau (p‐tau), specifically in female PS19 mice. RNAseq analysis identified cell ‐autonomous and non‐autonomous effects for microglial BIN1 during tau pathogenesis in the PS19 model. Weighted gene co‐expression analyses revealed complex networks of genes regulated by microglial gene expression during tau pathogenesis. We also identified gene networks correlated with levels of formic acid‐soluble p‐tau, irrespective of microglial Bin1 gene manipulation.ConclusionThese gene networks offer novel insight into microglial genes involved in responses to tau pathology, and the potential impact of BIN1 as a LOAD risk gene.
Impact of sex, ancestry, and local ancestry on Apolipoprotein E (APOE) for Alzheimer’s disease (AD): a pooled case‐control analysis of Alzheimer’s Disease Genetics Consortium (ADGC)
Authors: Rodriguez Omar Garcia , Wang Lily , Young Juan I ,   Alzheimer’s Disease Genetics Consortium (ADGC), Pericak‐Vance Margaret A , Martin Eden R. , Kunkle Brian W. 
Published: January 2025

AbstractBackgroundPrevious studies have reported that non‐Hispanic white (NHW) females carrying the APOE ε4 allele differ in risk of developing Alzheimer’s disease (AD) when compared to men. Recent studies suggest the association between APOE ε4 and AD risk may be modified by age and its local ancestry in admixed populations. However, there is still scant evidence on how sex could interact with these factors. We aimed to investigate the association of sex, ancestry, APOE, and local ancestry with AD in multiple cohorts.MethodsA pooled case‐control study was undertaken from 50 independent datasets (n = 30,539;age≥55years) in the Alzheimer’s Disease Genetics Consortium. Logistic regression models were used to study the associations between disease status and independent variables including age, sex, reported race (as a proxy of ancestry), and APOE genotype. Additionally, mixed models were implemented for the local ancestry APOE haplotype analyses among different ethnicities. A p‐value less than 0.05 was considered statistically significant.ResultsRegardless of ancestry, men and women with APOE ε3/ε4 or ε4/ε4 genotypes showed no significant difference in the risk of developing AD. When comparing subjects with APOE ε3/ε4 or ε4/ε4 (vs. ε3/ε3), East‐Asian (EA) males (OR,5.56; 95% CI:4.26‐7.60) and females(OR,5.46:4.34‐6.86) had the strongest ORs; whilst the weakest risk was for South‐Asian (SA) men(OR,1.14:0.99‐2.57) among all races/ethnicities. Age‐stratified analyses showed that NHW females(OR,5.36:4.74‐6.07 vs. males: OR,4.72:4.10‐5.60) had a higher risk of developing AD between ages 66‐75; whereas African American (AA), EA and SA exhibited this pattern at 55‐64. In Hispanics, the relationship is reversed, with males aged 55‐65 years carrying APOE ε3/ε4 or ε4/ε4(OR,4.53:1.67‐12.30: vs. females: OR,3.03:1.59‐5.78) having a stronger association with AD risk than their counterpart. No differences were found when stratified by sex and age for APOE ε2 and AD. Local ancestry (European ‐EU‐; African ‐AF‐; Amerindian ‐AI‐; and EA) analyses are being conducted by ancestry and sex.Preliminary analyses suggest differences by sex and local ancestry for APOE ε4.ConclusionsOur findings suggest differences by sex and reported ancestry in the risk for developing AD in carriers of APOE ε4. Global, local ancestry and sex should be considered in predicting risk due to APOE alleles.
Sex‐stratified GWAS for Alzheimer’s Disease Reveals African Ancestry Risk variants in Men
Authors: Belloy Michael E. , Reid Danielle M. , Guen Yann Le , Napolioni Valerio , Greicius Michael D 
Published: January 2025

AbstractBackgroundSeveral studies have indicated sex‐specific genetic risk for Alzheimer’s disease (AD), but these were centered on non‐Hispanic White individuals of European ancestry. We sought to identify sex‐specific genetic variants for AD in non‐Hispanic and Hispanic subjects of admixed African ancestry.MethodParticipants were ages 60+, of African ancestry (≥25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed or whole genome sequencing (WGS). Genome‐wide association studies (GWAS) were performed per data type, sex, and Hispanic/non‐Hispanic status (Table‐1), requiring genotyping rate ≥80% and minor allele frequency ≥1%, followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). A sex‐by‐SNP interaction model was also evaluated. GWAS performed multiple linear regression on an AD‐age score (Le Guen & Belloy et al. 2021; Figure‐1), adjusting for APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Variants were filtered to be covered on at least half of the individuals per stratum.ResultWe found 3 genome‐wide significant loci in men (Figure‐2) with lead variants 1) rs74853649 ∼85kb downstream of FHIT, 2) rs73411425 in the PILRA/ZCWPW1/NYAP1 AD risk locus, and 3) rs3736450 intronic on WWOX. Despite that rs73411425 is within a known locus, the variant is novel. Notably, all three variants showed significant sex‐by‐SNP interactions and were specific to African rather than European ancestry (Table‐2). Further, in men, we also observed a suggestive association intronic on RBFOX1, which was previously implicated as a risk gene harboring variants associated with higher amyloid burden in brain (Raghavan et al. 2020), with strongest effect sizes in African‐American individuals (those samples were independent of the current data).ConclusionThe study is an initial exploration of sex‐specific genetic effects in African ancestry individuals and warrants replication in larger data. Importantly, we show the relevance of expanding beyond non‐Hispanic white samples for sex dimorphism research, identifying male‐specific risk variants that have elevated frequencies in African ancestry, while being rare in other ancestries. In ongoing work, we are performing cross‐ancestry meta‐analyses of sex‐stratified GWAS followed by sex‐stratified omics integration to increase power to uncover sex‐specific genes relevant to AD.
Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease
Authors: De Jager Philip L. 
Published: January 2025

AbstractBackgroundRecent studies have revealed diverse Alzheimer’s disease (AD)‐associated cell states, yet when and how they impact the causal chain leading to AD remains unknown.MethodTo reconstruct the dynamics of the brain’s cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single‐nucleus RNA‐seq profiles. We associated glial, vascular and neuronal subpopulations with AD‐related traits for 437 aged individuals and aligned them along the disease cascade using causal modeling.ResultWe identified two distinct lipid‐associated microglial subpopulations, one associated with amyloid‐β proteinopathy while the other mediated the effect of amyloid‐β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment, we devised the BEYOND methodology, which uncovered two distinct trajectories of brain aging defined by differing sequences of changes in cellular communities. Our set of prospectively autopsied older individuals is separated into one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with either (1) AD dementia or (2) alternative brain aging.ConclusionWe provide a cellular foundation for a new perspective on AD pathophysiology that could inform the development and personalization of new therapeutic interventions targeting cellular communities while personalizing clinical management for those individuals on the path to AD or to alternative brain aging.
Synaptic plasticity dysregulation driven by pathogenic tau
Authors: Pareja‐Navarro Kristeen A. , King Christina D. , Kauwe Grant , Lokitiyakul Doyle , Sharma Mahima , Wong Ivy , Ngwala Yani , Schiling Birgit , Tracy Tara E. 
Published: January 2025

AbstractBackgroundSynapses can modify their strength in response to activity, and the unique properties of synapses that regulate their plasticity are essential for memory. Long‐term potentiation (LTP) is considered the physiological basis for how neurons encode new memories. A complex series of postsynaptic signaling events in LTP is associated with memory deficits in tauopathy models, but the mechanism by which pathogenic tau inhibits plasticity at synapses is unknown. Here, our objective was to delineate the postsynaptic mechanisms by which pathogenic tau inhibits LTP in neurons.MethodWe used human induced pluripotent stem cell (iPSC)‐derived neurons with mutations on tau that cause frontotemporal dementia or we treated human iPSC‐derived neurons with tau oligomers to model tau‐related pathogenesis. We induced NMDA receptor‐dependent LTP in the neurons and monitored trafficking of AMPA receptors (AMPARs) to the postsynaptic surface. To identify the mechanisms underlying synapse dysregulation, we designed an approach to detect changes in the postsynaptic proteome with high temporal resolution using APEX‐mediated proximity labeling and mass spectrometry.ResultPathogenic tau inhibited the delivery of AMPARs to the postsynaptic surface and blocked LTP expression in human iPSC‐derived neurons. The postsynaptically‐targeted APEX platform mapped the dynamic changes in the postsynaptic proteome of neurons with pathogenic tau.ConclusionOur findings reveal new mechanistic insights into how pathogenic tau alters the postsynaptic proteome and inhibits synaptic plasticity.