bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal transcriptomic similarities and differences among mouse models of amyloidosis
Authors: Paes Rodrigo Sebben , Carello‐Collar Giovanna , Limberger Christian , De Bastiani Marco , Baldasso Gabriela Mantovani , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundAnimal models of amyloidosis have been instrumental in Alzheimer’s disease (AD) research since they can resemble pathophysiological features of human AD. Nevertheless, each model is generated through different genetic engineering strategies, resulting in distinct phenotypes. In this context, whether AD core molecular programs are conserved among mouse models remains to be addressed. Herein, we aimed to explore similarities and differences among the transcriptomic of three mouse models of amyloidosis.MethodWe obtained hippocampal transcriptomics data from the Gene Expression Omnibus (GEO) repository of two transgenic mouse models (APP/PS1 and 3xTg‐AD mice), and the AMP‐AD Knowledge Portal of one knock‐in mouse model (hAß‐KI mice). The GEOquery package was used to download data from GEO and data from the AMP‐AD Knowledge Portal were downloaded with synapser and synapserutils packages. Next, we performed gene expression analysis to obtain the differentially expressed genes (DEGs, FDR‐adjusted p‐value < 0.05). We also determined the intersection of DEGs among models. Then, we performed functional enrichment analysis (FEA) to obtain Gene ontology (GO) terms of Biological Processes (GOBP) using the enrichGO function of clusterProfiler package (v3.16.1).ResultWe found 5055, 1073, and 162 DEGs in the APP/PS1, 3xTg‐AD, and hAß‐KI mice, respectively (Fig. 1A). APP/PS1 and 3xTg mouse models presented more overlapping DEGs (433 DEGs shared, Fig. 1A). Interestingly, only four genes were consistently differentially expressed across all mouse models (VGF, CORT, EDEM1, and C4B). The FEA revealed multiple enriched GOBP terms in each model [1609 in APP/PS1, 1685 in 3xTg‐AD, and 25 in the hAß‐KI, adj. p‐value <0.1, and 16 GOBP terms overlapping across the three AD mouse models (Fig. 1B).ConclusionIn this study, we demonstrate that APP/PS1 and 3xTg‐AD exhibit greater transcriptomic similarities between each other than with hAß‐KI. Only four DEGs were consistently identified in all models. However, despite this, the three models show common alterations in 16 biological processes. These findings collectively indicate that, at the biological processes level, transgenic mouse models carrying autosomal dominant Alzheimer’s disease traits and a knock‐in (KI) mouse model share common pathophysiological features, being suited for translational studies.
Measuring The Speed and Accuracy of Semantic Retrieval with the Semantic Stroop Task
Authors: Kahly Omar , Hall Kathleen , Baldo Juliana , Schendel Krista , Herron Timothy J , Geraci Kristin , Blank Michael , Jaramillo Isabella , Williams Garrett , Miranda Miranda , Chok Jas M. , Lwi Sandy J. , Curran Brian , Santavicca Isabella , Thomas Lexie , Spinelli Maria G , Johnson David K , Woods David L. 
Published: January 2025

AbstractBackgroundSemantic memory assessments are sensitive indicators of cognitive decline in pre‐clinical Alzheimer’s Disease (AD), with slowed reaction time and diminished accuracy serving as markers for amyloid accumulation. We introduce the Semantic Stroop Test—a brief (4.3 minute), automated semantic retrieval and executive function task included in the California Cognitive Assessment Battery (CCAB).MethodThe Semantic Stroop Test was administered to 572 healthy adults (50% female, Age = 65.6 years, ±10.6). Participants were tested in their homes using tablet computers. Two sessions were administered on consecutive days, with tests remotely monitored (Figure 1).Participants were instructed to produce an antonym in response to words in red font and a synonym in response to words in blue font. Sixteen words were presented in random order (Figure 1). Then the same 16 words were presented again in opposite colors. Verbal reaction time (RT) and response accuracy were quantified for each word.ResultThe Semantic Stroop Test showed excellent test‐retest reliability (r = 0.71 accuracy, r = 0.82 RT) and switch failure detection (r = 0.47) in tracking errors. A multiple regression model revealed significant effects of Age and Vocabulary (p<0001) on Accuracy and accounted for 41% of the variance. RT analysis also showed significant effects of both Age and Vocabulary (p<.0001) as well as Education (p<.05), with the model accounting for 30.1% of the variance. Faster RT was associated with higher Accuracy (r = ‐.51) (Figure 2). Furthermore, subjects with consistent sequential responses (e.g., synonym‐synonym) were more accurate than response‐switch trials. Subjects were also more accurate in response to antonym‐based cues than synonyms with 88% vs 79% correct.ConclusionThe Semantic Stroop Test demonstrates excellent psychometric properties. It reliably captures age‐related cognitive effects through accuracy and speed measures of semantic retrieval while remaining sensitive to executive function processes such as cue‐based switching.
African ancestry component could change APOE4 effect size for AD of a diverse population
Authors: Bicalho Maria Aparecida Camargos , VIANA BERNARDO DE MATTOS , Cintra Marco Túlio , Hansen Erika de Oliveira , Burgos Ivonne Carolina Bolaños , Engelmann Gabriela Tomé Oliveira , de Miranda Debora Marques , Romano‐Silva Marco Aurélio , Parveen Kayenat , Dalmasso Maria Carolina , de Marco Luiz Armando Cunha , Ramirez Alfredo 
Published: January 2025

AbstractBackgroundWorldwide, the actual number of 55 million people diagnosed with dementia is estimated to increase to 139 million people affected by dementia in 2050. 61% of these individuals resided in low and middle‐income countries (LMIC). Genetic risk factors account for up to 80% of the attributable risk of Alzheimer’s disease (AD), the leading cause of dementia. Thus, one can argue that most of the pathophysiological pathways in AD are driven by genetic determinants. Despite the increasing number of dementia cases in LMIC, poor generalizability of genetic studies across populations arises from the abundance of studies focused on European descent and the lack of studies in globally diverse populations.MethodWe developed a case control study, including older adults selected from Cog‐aging Research Group of the UFMG, Brazil, divided in two groups: control and AD (AD and AD plus vascular dementia). They were submitted to the same neuropsychological and geriatric protocols. Diagnosis of AD dementia were based on Mckhann criteria. DNA samples were subjected to genome‐wide‐genotyping using the Infinium Global Screening Array (Illumina). Quality controls were performed using PLINK and R. After QC, remaining samples were analyzed for population stratification. TOPMed imputation server was used to perform imputation. Principal components (PC) analysis considered phenotype, sex, and age.ResultThe final sample was composed by 573 samples, 181 controls and 309 cases, 389 female and 184 males. Our sample was composed predominantly by Caucasian and African genetic ancestries (Figure 1). From 23 top hit variants, only APOE4 allele reached significant values (Figure 2), with an effect size lower than that observed in other populations (p = 1.06E‐08; B = 1.42). Haplotype analysis of the APOE region revealed that two other variants (chr19:44906745:G:A and chr19:44918903:C:G), which have shown lower MAF in African than in Caucasian population, could change the APOE4 effect in our population (Figure 3).ConclusionOur sample is composed by a heterogeneous genetic ancestry, different from the other Latin America populations. APOE4 allele presented a lower effect size to AD than some other populations. This result could be related to two other variants, associated with the African component, influencing the effect of APOE4 allele.
Selective Vulnerability to Tau Pathology in Serotonergic Dorsal Raphe Nucleus Neurons
Authors: Cooper Benjamin J , Hunter Mikayla L , Pierson Samantha R , Marcinkiewcz Catherine A , Hefti Marco M , Fiock Kimberly L 
Published: January 2025

AbstractBackgroundThe dorsal raphe nucleus (DRN) is the primary source of serotonergic projections to supratentorial structures. We and others have shown that it is selectively vulnerable to tau pathology in both human and mouse models of early AD. Although well characterized in mice, the neurochemical anatomy of the human DRN, and in particular the role of Vesicular glutamate transporter‐3 (VGLUT3)‐expressing neocortical projection neurons in tau pathology, remains unclear.MethodPost‐mortem human brain tissue was obtained from previously consented cases stored in the Iowa Neuropathology Resource Laboratory. Next of kin provided consent for research use of tissue. Sections were processed, embedded in paraffin, and sectioned in the usual fashion. Tyrosine hydroxylase (TH), tryptophan hydroxylase 2 (TPH2), and phosphorylated tau (AT8) were visualized by immunofluorescence, while VGLUT3 transcripts were identified by RNA in situ bybridization. Imaging was done using a Cytation5 platform with downstream analysis using MATLAB and R.ResultWe found that, similar to mice, the human dorsal raphe has both VGLUT3‐positive and –negative serotonergic neurons. Unlike mice however, in the human DRN, these are not anatomically separate, and the proportion of TPH2 neurons that are VGLUT3 appears to be higher than in mice. In patients with DRN tau aggregates, these appear to selectively affect TPH2+/VGLUT3+ neurons.ConclusionSerotonergic neurons in the dorsal raphe express high levels of VGLUT3, with an anatomic distribution differing from that seen in mice, and these neurons appear to be selectively vulnerable to tau pathology.
Epigenetics and Alzheimer’s Disease: A Literature Review
Authors: da Silva Bibiana Ruppenthal 
Published: January 2025

AbstractBackgroundIn recent years, researchers have linked epigenetic factors to numerous diseases, one of them being Alzheimer’s Disease (AD). Those factors may lead to the disease but also serve as a path for new treatments and prevention methods.MethodA wide selection of articles in the PubMed platform that focused on epigenetics, Alzheimer’s Disease, and correlating aspects among them were reviewed.ResultPrevious studies have shown that the main epigenetic factors associated with AD are diet and nutrition, exercise, and stress. An anti‐inflammatory diet rich in copper and zinc results in a decrease in the development of AD since the dysregulation of the nutrients leads to the modification of the amyloid metabolism known to participate in the pathogenesis of AD. At the same time, neurodegeneration may be reduced by up to 45% with the practice of physical exercise, showing that the molecules created by the stimulation could allow discoveries on physiological pathways and non‐drug therapy for prevention. Studies have also found that catecholamine and corticosteroid systems in late‐onset AD can be caused by early life stress. Moreover, epigenetic changes are prone to happen during the prenatal stage and childhood, which indicates the importance of the aspects mentioned in the entire life and not only during the adult years. The absence of the factors mentioned previously could lead to epigenetic mechanisms that modify chromatin and gene expression. These mechanisms are histone acetylation, microRNA, DNA methylation, and histone methylation. The most important ones for AD are the last two that are responsible for silencing gene expression, especially gene APOE, crucial for the amyloid β downstream effect on the aggregation of phosphorylated tau in the brain, and when histone H3 is methylated, it affects synaptic transmissions, shaft bursts, and nerve development, and the trimethylation of histone H3 lysine K4 is associated with the expression of genes related to memory and the protein Zif268 that helps to maintain long‐term potentiation in the recognition memory, respectively.ConclusionOverall, epigenetics is a significant area of study to understand the cause of AD and to discover new methods for prevention, diagnosis, treatment, and hopefully one day cure.
Histofluorescence analysis of Pittsburgh Compound B labeled pathology in Down syndrome putamen and frontal cortex
Authors: Rouanet Jeremy P. , Ngo Kim Chan , Shamas Tamara M , Phelan Brenna , Fung Ashley L. , Phelan Michael J. , Pascual Jesse R. , Ngo Phong , Andrews Elizabeth J. , Wright Sierra , Lai Florence , Kofler Julia , Ikonomovic Milos D , Head Elizabeth ,   Alzheimer Biomarkers Consortium ‐ Down Syndrome (ABC‐DS)
Published: January 2025

AbstractBackgroundBrain deposits of amyloid‐β (Aβ), one of the hallmark pathologies of Alzheimer disease (AD), are consistently present in people with Down syndrome (DS) after the age of 30 years. Positron emission tomography (PET) radioligands like [3H]Pittsburgh Compound‐B (PiB) allow for visualizing Aβ accumulation in living people. In DS, the earliest and strongest PiB‐PET retention is in the striatum, differing from late‐onset AD. The neuropathological substrates of early PiB retention in DS striatum are unknown. The goal of this postmortem study is to compare histofluorescent labeling with cyano‐PiB, a fluorescent derivative of PiB, in the striatum and frontal cortex of people with DS.MethodCyano‐PiB histofluorescence load (% area) was evaluated on postmortem tissue from putamen and frontal cortex (n = 43; age 42‐70 years, 24F/19M) using whole slide imaging and digital quantification. Cyano‐PiB histofluorescence was combined with Aβ immunofluorescence on a subset (n = 3) of cases.ResultAfter the age of 42 years, cyano‐PiB loads did not increase as a function of age at death in frontal cortex (layers II‐IV; p = 0.64) and putamen (p = 0.76). Cyano‐PiB loads were not greater in putamen compared to frontal cortex. Putamen and frontal cortex cyano‐PiB loads directly correlated (r = 0.52). Cyano‐PiB labeled plaques were immunolabelled with Aβ‐targeting antibodies 6E10, 12F4, and 4G8, in both putamen and frontal cortex, with less overlap observed in deep frontal cortical layers.ConclusionStriatal cyano‐PiB load in putamen was not greater than in the frontal cortex layers II‐IV in people with DS above the age of 42 years. The partial overlap of cyano‐PiB labeled amyloid plaques with Aβ immunoreactive plaques suggests that only a subset of Aβ plaques were detected with cyano‐PiB. Further characterization of cyano‐PiB loads in deep layers of the frontal cortex as well as in DS cases at younger ages is warranted.
Validation Of the Tau Heterogeneity Evaluation in Alzheimer’s Disease (THETA) Score Using Longitudinal and Histopathology Data
Authors: Gebre Robel K , Moscoso Alexis , Raghavan Sheelakumari , Wiste Heather J. , Heeman Fiona , Costoya‐Sánchez Alejandro , Schwarz Christopher G. , Spychalla Anthony J. , Lowe Val J. , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Schöll Michael , Murray Melissa E. , Jack Clifford R. , Vemuri Prashanthi 
Published: January 2025

AbstractBackgroundWe recently developed a novel tau‐PET summary measure THETA, capturing regional heterogeneity and identifying tau status, using ground truth visual assessments from a large single‐center cross‐sectional dataset and validated on independent cohorts [1, 2]. In this study, we aimed to evaluate the performance of THETA on longitudinal and histopathology data.MethodWe included longitudinal tau‐PET ([18F]flortaucipir) data from 696 Mayo Clinic Study of Aging (MCSA) and ADRC participants, with histopathology in n = 90. Fig. 1 shows the model that uses regional standard uptake value ratios (SUVR) and a target of binary class of tau positivity for prediction of THETA. This model was applied to predict tau status on each followup scan. Slopes of the meta‐ROIs’ tau SUVRs and THETA were evaluated by diagnostic group and as a function of baseline amyloid SUVR in discordant CU participants (where meta‐ROI and visual assessments did not match at baseline) and in incident‐THETA+ CU participants (whose THETA moved from below to above 1 over serial tau‐PET scans). We evaluated tau measurements as a function of Braak stages for neurofibrillary tangles.ResultLongitudinal plots of meta‐ROIs for diagnostic groups were very similar, but the expanded range of THETA based on visual positivity prediction clearly identified tau positive or tau‐negative scans. In discordant‐CU (n = 97) and incident‐THETA+ CU participants (n = 14 all amyloid positive at follow‐up but only 65% at baseline), the relationship between baseline amyloid and rate of tau increase was stronger for THETA than temporal meta‐ROI (Fig. 2). Separation between baseline and follow‐up was greater for THETA (t‐statistics = 90) compared to temporal meta‐ROI (t‐statistics = 20) (p<0.01) in the incident‐THETA+ CU participants. THETA showed a slightly stronger association with Braak stage than meta‐ROIs (rho = 0.87 vs. ≤0.83, p<0.05), with better separation of clinical diagnoses (Fig. 3).ConclusionTHETA remained clearly negative or positive in MCI and AD, providing consistent information on underlying etiology of impairment at both baseline and follow‐up. Although binary in its construction, THETA both provided separation of values based on tau status and its change correlated with baseline amyloid burden especially in discordant‐CU where tau deposition is not in typical meta‐ROIs. Further work is needed to confirm if THETA captures early tau changes.
Blood‐Based Biomarkers to Aid in Alzheimer’s Disease Prediction or Diagnosis: Analysis in a Multi‐Ethnic Cohort Study
Authors: Bahl Aanya , Honig Lawrence S. , Kang Min Suk , Sanchez Danurys , Reyes‐Dumeyer Dolly , Manly Jennifer J. , Lantigua Rafael A. , Dage Jeffrey L. , Brickman Adam M. , Vardarajan Badri N. , Mayeux Richard , Gu Yian 
Published: January 2025

AbstractBackgroundBlood‐based biomarkers may aid in the diagnosis of Alzheimer’s Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well‐tested in community populations. In the current study, we aimed to determine whether blood‐based biomarkers can aid in refining a multi‐ethnic, urban clinically diagnosed AD community‐based cohort.MethodWe included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross‐sectional study. Six biomarkers, including phosphorylated‐tau‐181 (P‐tau181), total (T‐tau), amyloid‐beta 40 and 42 (Aβ40, Aβ42), Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain (NfL) were measured using Quanterix SIMOA HD‐X platforms. The association between the biomarkers and AD or cognitive impairment was tested using logistic regression, adjusted for age, sex, ethnic group, and years of education. Individuals were subsequently characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores.ResultThe mean age of individuals was 79.3 years (6.56) and 379 (69.4%) were women, 133 (24.48%), were Non‐Hispanic Black, 153 (28.0%) Non‐Hispanic White, and 248 (45.4%) were Hispanic. A clinical diagnosis of AD was made in 129 (25.49%) individuals. Low Aβ42 (OR = 0.18, [95% CI: 0.04 ‐ 0.92]), low Aβ42/Aβ40 (OR = 0.49, [95% CI: 0.228 ‐ 0.872), and high P‐tau181/Ab42 (OR = 5.494, [95% CI: 1.523 – 20.416]) were associated with a clinical diagnosis of AD suggesting a role as predictive biomarkers. However, the best combination, GFAP and P‐tau181/Aβ42 cut scores, yielded a sensitivity of 41% and specificity of 70.5% for clinically diagnosed AD. The concordance was 54.5% and the discordance was present in both directions. Low education, cardiovascular and other comorbidities might contribute to the discrepancy between biomarker positivity and clinical diagnosis.ConclusionWhile GFAP and P‐tau181/Aβ42 levels are associated with AD pathology and can aid in the diagnosis of AD, the presence of multiple chronic conditions may lead to either false positives or negatives. Large multi‐ethnic community cohort studies are needed to further examine the utility of these biomarkers in aiding in the clinical diagnosis of AD.
Integrative approach to profile resilience and risk factors in Alzheimer’s disease
Authors: Is Ozkan , Bergman Jeremiah , Wang Xue , Tutor‐New Frederick Q , Is Ozkan , Quicksall Zachary , Atik Merve , Reddy Joseph S. , Duvuuri Venkata N.S. , Min Yuhao , Gao Junli , Sotelo Katie D , Nguyen Thuy , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilüfer 
Published: January 2025

AbstractBackgroundA complex, multicellular disease with genetic and immunological elements, Alzheimer’s disease (AD) affects millions worldwide. There has been previous research linking AD to the missense variants ABI3‐rs616338‐T and PLCG2‐rs72824905‐G, and the altered expression of these genes has been shown to disrupt microglial function. In our understanding of AD risk and resilience, limited research has been conducted on how these variants affect microglial subtypes and states in AD.MethodsWe previously identified DOCK8 protein as a target for fluorescent activated nuclei sorting (FANS) to enrich microglia nuclei from frozen human brains. Using this enrichment strategy, we generated microglia enriched snRNAseq data from temporal cortex tissue of 30 donors harboring ABI3 or PLCG2 missense mutations, or neither mutation. We introduced PLCG2 variant in either homozygote, and heterozygote forms into an AD patient derived iPSC through CRISPR/Cas9 approach, differentiated these cells into microglia cells (IMGLs) following established protocols, and generated scRNAseq data after treatment with Amyloidβ. We applied standard alignment and quality control pipelines to the snRNAseq and scRNAseq datasets in parallel. Established markers of microglia states and subtypes were utilized to annotate the clusters; analyzed for their hub gene expression using comparisons between cluster differential profiling to determine signature pathways. Differential gene expression was assessed using pseudo bulk and MAST approaches.ResultsWe obtained single nuclei transcriptome profiles of 54,000 frozen human brain nuclei, of which 35,000 are microglia, through snRNAseq, and single cell profiles of 63,000 iMGLs through scRNAseq, using our standard alignment and quality control procedures. Our differential gene expression analysis identified novel genes and pathways which were identified as part of resilience or AD risk networks in microglia subtypes and states. These alterations were validated using orthogonal experimental methods and further explored for their conservation using in vivo external datasets. Pseudotime inference will be completed to probe microglia marker gene expression dynamics, treatment conditions, along with continuous cell‐state changes.ConclusionOur study uncovers microglia subtype specific resilience and risk factors provided by AD related genetic variants using snRNAseq from frozen human brain and scRNAseq from IPSC derived microglia cells. These findings nominate novel targets and pathways with therapeutic potential.