bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spastic paraplegia leading PSEN1‐related familial Alzheimer’s disease in Italy
Authors: Meyyazhagan Arun , Basavaraju Preethi , Miele Marialuisa , Kawarai Toshitaka , Panza Emanuele , Orlacchio Antonio 
Published: January 2025

AbstractBackgroundWe researched the occurrence, neuropathology, and clinical features of spastic paraplegia (SP) associated to dementia in presenilin 1 (PSEN1) Italian patients related to familial Alzheimer’s disease (AD).MethodsWe carried out whole exome sequencing in 33 familial AD probands with hereditary spastic paraplegia (HSP) that resulted negative for the identification of pathogenetic variants in known HSP genes. One patient was identified with a DNA variant in PSEN1, and bioinformatic analysis was conducted to characterize its pathogenetic nature. Furthermore, brain biopsy was executed once he deceased. Bioinformatic analysis was conducted to characterize the new variant.ResultsThis research yielded the identification of one novel PSEN1 pathogenic variant. Notably, the same affected individual revealed SP at 22 years of age and 23 years later developed AD. Amyloid deposition with diffuse cortical plaques was described on brain biopsy. Differently from previous reports, we found that Italian PSEN1 patients displaying primarily as SP have an earlier age of onset and are associated with mutations located before codon 200.ConclusionThe outcomes of this study increase the clinical and mutational landscape associated with PSEN1‐related familial AD. Expanding results of different populations, we strongly recommend PSEN1 genetic testing in affected subjects having SP with no variants in known HSP‐related genes, mostly when linked with a family history of AD.
A machine learning approach to multifactorial modeling of episodic memory performance
Authors: Fletcher Evan , Chanti‐Ketterl Marianne , Hokett Emily , Lor Yi , Venkatesan Umesh M , Gilsanz Paola , Whitmer Rachel A. , Chen Ruijia , George Kristen M. , Zlatar Zvinka 
Published: January 2025

AbstractBackgroundNeurocognitive health is influenced by multiple modifiable and non‐modifiable lifestyle factors. Machine learning tools offer a promising approach to better understand complex models of cognitive function. We used extreme gradient boosting (XG Boost), an algorithm of decision‐tree modeling, to analyze the association between 15 late‐life lifestyle and demographic factors with episodic memory performance.MethodOur dataset consisted of 2247 participants from the KHANDLE and STAR cohorts. Participants included 841 men and 1406 women, an ethnoracial diversity of 413 Asian, 987 Black, 349 Latinx, and 496 White adults with age range 54‐90 (mean = 74). XG Boost models of continuous episodic memory performance were trained and evaluated using a random training/test split of the data. Trained models were used to plot relative factor importance and individual Shapley values for each participant, over the entire sample and stratified by gender.ResultWe present XG boost ranking of factors for episodic memory in the full set and stratified by gender. The relative importance of factors for baseline episodic memory (Fig. 1) showed education, income range and sleep quality as the most important variables in both full and sex‐stratified models. In the full sample, gender was highly important and ethnoracial categories showed the least importance.Shapley values for each variable (Fig. 2) showed gender, education, income range, volunteering, and sleep quality were paramount contributors to episodic memory performance. In gender‐stratified models, education, volunteering, income, and sleep quality were of most importance. Exercise contributed modestly. Negative factors like smoking, excessive alcohol and TBI had moderate impacts. Ethnoracial background had minimal influence, except for White (full set) and Latinx (male and female).Shapley dependency on memory in the full set (Fig. 3) showed a plateau effect for education at around 12 years of schooling; linearly increasing effect with no plateau for income; an inverted “U” dependence on sleep duration; and a nonlinear relation with sleep quality requiring more investigation.ConclusionDecision trees may be a promising approach to determining the relative contributions of multiple life exposure factors that affect cognitive performance in a large and diverse cohort. This may help to inform ADRD preventive interventions.
Utility of three cognitive screening tests to triage referrals to a dementia specialty clinic
Authors: Hilsabeck Robin C. , Benge Jared F , Scott Bonnie M , Thotakura Soumya , Rana Amtul‐Noor , Schmitz Suzanne 
Published: January 2025

AbstractBackgroundDue to the shortage of healthcare professionals with expertise in diagnosis and treatment of Alzheimer disease and related dementias, there are long wait times to be evaluated in dementia specialty clinics and no clear guidance about how to allocate limited resources. The purpose of this study was to examine utility of cognitive screening measures administered by clinic staff to determine level of cognitive impairment to aid in decisions about which patients may benefit from full diagnostic services.MethodsParticipants were 169 older adults who completed an intake interview, including a brief cognitive screening test, conducted by a neuropsychologist at a dementia specialty clinic. During the rooming process, clinic staff administered one of three cognitive screening measures, Quick Dementia Rating Scale (QDRS; n = 47), Quick Mild Cognitive Impairment (Qmci) screen (n = 70), and the BrainCheck Standard Battery (n = 52). After the intake interview, blinded to results of these cognitive screening measures, the neuropsychologist completed an initial impressions form indicating level of cognitive impairment (i.e., none, mild, possible dementia, definite dementia). A separate neuropsychologist, blinded to information from the intake interview, completed the same form based on results of each of the three cognitive screening measures and patient demographic information.ResultsBased on impressions from the intake interview, 27 patients were cognitively normal (CN), 67 had mild cognitive impairment (MCI), 32 had possible dementia, and 43 had definite dementia. Agreement on level of cognitive impairment between the intake interview and cognitive screening measures was 53% for QDRS (κ = .459, p < .001), 41% for Qmci (κ = .423, p < .001), and 48% for BrainCheck (κ = .539, p < .001). Agreement improved notably for all three measures when level of cognitive impairment was limited to two groups (i.e., CN + MCI vs possible + definite dementia): 79% for QDRS (κ = .566), 77% for Qmci (κ = .537), and 83% for BrainCheck (κ = .655).ConclusionsCognitive screening measures administered by clinic staff and interpreted by dementia experts may have utility as time‐efficient, cost‐effective clinical decision support tools for the allocation of limited dementia diagnostic resources.
Systematic dissection of the genomic mechanisms underlying differential tauopathy risks associated with the human 17q21.31 locus
Authors: Qi Le , Pedicone Chiara , Bowles Kathryn , Yin Jiani , Goate Alison M. , Geschwind Daniel H. 
Published: January 2025

AbstractBackgroundThe genetic association between 17q21.31 and increased risk for tauopathies, such as Progressive Supranuclear Palsy, is well established. However, the mechanisms driving the differential disease risks between two major haplotypes, H1 and H2 are unclear. This is mainly due to a 970KB inversion between H1 and H2 haplotypes, leading to a 1.5Mb region where strong LD confounds the identification of causal variants, as well as our understanding of the gene regulatory mechanisms contributing to disease.MethodTo identify genetic and epigenetic changes between the H1 and H2 haplotypes that drive neurodegeneration, we obtained homozygous H1/H1 and H2/H2 iPSCs from healthy donors with European ancestry. We performed comprehensive genomic profiling, including RNA‐seq, ATAC‐seq and Hi‐C on neurons, astrocytes and microglia independently derived from iPSCs. Differentially expressed genes, accessible chromatin regions (DARs) and chromatin interactions were analyzed between H1/H1 and H2/H2 cells. Integration of different modalities was done to uncover causal H1/H2‐associated variants and their effects on gene regulatory mechanisms.ResultWe identified 6682 and 8603 genome‐wide DARs, as well as 5 and 27 DARs at the 17q21.31 locus in H1/H1 and H2/H2 neurons respectively. In H2 neurons, genes with reduced accessibility relative to H1 neurons, in either promoters or distal enhancers, showed enrichment in Gene Ontology terms associated with axon development and synaptic signaling; genes with increased relative accessibility in H2 neurons were associated with cell cycle and immune responses. Transcription factor (TF) binding motif analysis showed that neuronal differentiation‐related TFs were enriched in DARs reduced in H2 neurons. We detected reduced accessibility in MAPT promoters in H2 neurons, consistent with previous findings. We identified several H1/H2 haplotype‐divergent SNPs within the MAPT promoter peak, that disrupt binding motifs for N‐MYC, CTCF, SP2 and AP‐2.ConclusionThrough analysis of chromatin accessibility, we pinpointed several pathways involved in neuronal signaling that differentiate neurons from H1/H1 and H2/H2 individuals, including DARs at the MAPT locus that likely account for reduced expression on H2 haplotypes. We also identified several haplotype‐divergent SNPs predicted to interrupt TF binding required for MAPT expression. Both of these changes potentially contribute to reduced risk for tauopathy in H2/H2 individuals.
Inflammasome Signaling in Alzheimer’s Disease after Traumatic Brain Injury
Authors: Vaccari Juan Pablo de Rivero , Cabrera Ranaldi Erika d.l.R.M , Johnson Nathan H , Kerr Nadine A , Bramlett Helen M , Keane Robert W , Dietrich W Dalton 
Published: January 2025

AbstractBackgroundThe global ageing population is rising with each year, and with that, the percentage of individuals with Alzheimer’s disease (AD) is expected to rise in parallel. Along with age, traumatic brain injury (TBI) is another risk factor for AD. TBI and AD patients demonstrate abnormal inflammatory responses, including that of the inflammasome. The inflammasome is a multi‐protein complex of the innate immune system, that leads to the release of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 through caspase‐1 and apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). Pyroptosis, a form of inflammatory cell death, also occurs via gasdermin‐D cleavage by caspase‐1. Our laboratory has previously demonstrated that genetic predisposition to AD can worsen acute inflammasome activation and outcome after TBI, but the chronic effects of TBI with AD have not been studied.MethodThe 3xTg model of early‐onset familial AD was used, along with their B6129SF2 (WT) controls. AD and WT mice underwent either sham surgery or controlled cortical impact (CCI) and were sacrificed 3‐months post‐injury. Cortical lysates were collected and probed for inflammasome proteins and pro‐inflammatory cytokines via immunoblotting and ECLIAs. Brain sections were utilized for volumetric analysis and immunohistochemistry for inflammasome proteins and degenerative markers.ResultThere was a significant increase in chronic IL‐1β in AD/TBI mice that was not present in WT/TBI mice. Furthermore, there were also increased levels of the inflammasome proteins NLRP3, caspase‐8, and ASC at 3‐months post‐injury in AD/TBI vs WT/TBI mice. AD/TBI demonstrated elevated expression of GFAP, a marker of astrogliosis, which co‐localized with ASC in immunohistochemical analyses. Injured mice showed increased neurofilament light protein, which also co‐localized with ASC. Finally, AD/TBI mice had significant loss of total cortical and hippocampal volume compared to WT/TBI mice.ConclusionOur findings establish a chronic dysfunctional inflammatory response in TBI with a genetic predisposition to AD that is not seen in TBI alone. This suggests a unique injury progression that is affected by genetic predisposition to AD that calls for specialized treatment. In addition, due to the increased inflammasome response seen in our results, our conclusions indicate a promising role for the inflammasome as a treatment target.
Ferroptosis programmed cell death in AD‐derived neurons
Authors: Plascencia‐Villa German , Perry George 
Published: January 2025

AbstractBackgroundNeurodegeneration is characterized by the progressive loss of neurons. However, the mechanisms by which neurons die in Alzheimer’s disease (AD) remain elusive. Disrupted iron homeostasis is associated with accelerated cognitive decline, amyloid beta deposition, and AD progression, but its pathogenic relevance is poorly understood. The recent discovery of ferroptosis (an iron‐dependent regulated cell death mechanism) provides an alternative potential explanation for the relevance or iron dysregulation in AD.MethodAD‐derived neurons are used to determine neurotoxicity, morphological alterations and understanding of ferroptotic responses and progression. Neurons were dosed with ferroptosis‐inducing agents to determine susceptibility to oxidative stress and cellular responses.ResultWe performed oxidative stress assays to quantify glutathione (GSH/GSSG), reactive oxygen species (ROS), NAD/NADPH, lipid peroxidation, mitochondrial dysfunction and intracellular iron deposition in AD‐derived neurons. Furthermore, the neuronal responses to oxidative stress‐ferroptosis is visualized with live‐cell holotomography (quantitative phase microscopy) to determine the neuronal ferroptotic phenotype.ConclusionUnderstand the role of iron accumulation, oxidative stress, and cell‐specific susceptibility to ferroptosis programmed cell death in human brain cells and model the complex molecular responses related to neuronal loss in AD. These experiments provide the kinetics of biochemical, metabolic and morphological features of AD neurons under ferroptotic oxidative stress.
ApoE in brain mitochondria and energetics: From mice to human
Authors: Borkowski Kamil , Liang Nuanyi , Arnold Matthias , Bu Guojun , Kaddurah‐Daouk Rima , Zhao Na , Kanekiyo Takahisa 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) risk and progression are significantly influenced by ApoE genotypes, with ApoE4 increasing and ApoE2 decreasing the susceptibility compared to ApoE3. Understanding metabolic pathways affected by ApoE genotypes will help decipher disease development and identify new therapeutic targets.MethodThis study investigates the impact of ApoE genotypes on aging brain metabolic trajectories using human ApoE‐targeted replacement mice. Applying Biocrates P180 targeted metabolomics platform, we analyzed the metabolic impact of ApoE2/2, ApoE3/3, and ApoE4/4 on fatty acid β‐oxidation, amino acids, and phospholipids, which are known to be altered in AD. Furthermore, we compared our rodent model results with human dorsolateral prefrontal cortex data from the Religious Orders Study/Memory and Aging Project (ROS‐MAP).ResultWe found aging mice carrying ApoE2/2 had altered branch‐chain amino acid metabolism and increased C5 acylcarnitine and its ratio to precursor isoleucine, pointing towards increased β‐oxidation and branched‐chain amino acid (BCAA) utilization. Furthermore, ROS‐MAP data revealed the ApoE2 genotype affects similar areas of metabolism in humans. Additionally, our data provide comprehensive insight into age‐related metabolic changes of the current mice model, independent of ApoE genotype, among phospholipids, sphingomyelins, amino acids, and biogenic amines. Many of the observed differences are also known aging markers in humans, with a connection to cognition and Alzheimer’s disease.ConclusionTogether, these results suggest a potential involvement of ApoE2/2 genotype in energy metabolism and characterize the current mice model for further study of ApoE in AD, brain aging, and brain BCAA utilization for energy.
Naturally occurring human antibodies associated with AD and normal cognition
Authors: Reyes‐Ruiz Jorge Mauricio , Zhang Jizhi , Kumar Ashutosh , Yu Zhaoxia , Glabe Charles G 
Published: January 2025

AbstractBackgroundAnti‐ Aβ monoclonal antibodies are the first FDA‐approved treatments for AD that slow cognitive decline and lower Aβ plaques. Our goal is to identify the epitope specificities of antibodies in human blood that are associated with AD and NC and determine the predicted protein targets of these antibodies.Method101 AD (MMSE < 27) and 98 NC (MMSE > 27) serum samples were obtained from the UCI tissue repository. Epitomic profiling was conducted on the blood samples to define the epitopes for the antibodies in the samples by immunoselecting random 12 amino acid sequences from a phage display library. The resulting unique sequences are identified and their frequency counted. The 12mer sequences are tiled into tetramers and the resulting antibody‐specific tetramers are compared by Mann‐Whitney U test to identify differentially expressed epitope segments (DEES) that are upregulated in the AD and NC populations.ResultA large number of DEES (range 300 – 14,000 out of a total of 160,000 tetramers) was observed for AD and NC populations in both samples. Some of the DEES map to amyloids known to occur in AD, such as Aβ, tau, a‐synuclein, TDP43 and Tmem106b, but the actual epitopes are different in AD and NC. Both AD and NC populations’ data was then processed using UMAP for visualization and cluster analysis. Cluster analysis indicates that there are two clusters in the AD population: One large group that partially overlaps with the NC population and includes antibodies against the N‐terminus of Aβ and a well separated minor group that is defined by immunoreactivity to a heptameric linear epitope of currently unknown origin. The NC population includes several groups that contain anti amyloid antibodies.ConclusionHuman blood contains a large number of antibodies that are differently expressed in AD that recognize distinct amyloid and non‐amyloid epitopes. These antibodies may be protective for disease, predictive for presymptomatic disease onset and progression or antibodies in response to amyloid deposition that could be protective depending on the concentration or predictive of disease subtype. Further work is aimed at determining the significance of the different antibodies and validating their disease association
Agora: An openly available web resource to enable exploration of nascent therapeutic targets for Alzheimer’s disease
Authors: Britton Jessica S , Wiley Jesse C , Beck Jaclyn , Leal Karina , Yi Lawrence , Macdonald Brad , Do Khai , Simon Stockard , Swan Hallie , Grosenbacher Nicholas , Yu Thomas , Hodgson Jay , Greenwood Anna 
Published: January 2025

AbstractBackgroundAgora (https://agora.adknowledgeportal.org) is an openly available web resource developed to enable a broad spectrum of Alzheimer’s disease (AD) researchers access to target‐based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.MethodAgora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 950 potential therapeutic targets that have been nominated by the NIA’s Accelerating Medicines Partnership in AD (AMP‐AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome‐wide analyses of high‐dimensional human transcriptomic, proteomic, and metabolomic data; use interactive tools designed to enable non‐bioinformaticians to evaluate and compare complex multi‐omic data; and access the underlying data that drives the results and visualizations presented in the application.ResultAgora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) comparative and per‐target visualizations for SRM proteomic differential expression results and 2) enabling the discovery of TREAT‐AD Target Experimental Resources for supported targets.ConclusionThe advancement of promising new AD therapeutics requires efforts from research groups and specialties across both academia and industry. Agora enables the AD research community to develop and share target hypotheses that will accelerate the investigation of promising new AD therapeutic targets, pathways and mechanisms.
APOE4 Alters Tau Propagation in Regions Associated with Early Alzheimer’s Disease in a Humanized Mouse Model of Tau Spread
Authors: Arain Hirra A , Idiarte Juan F , Lama Tsering D , Figueroa Helen Y , Guo Jia , Duff Karen E , Nuriel Tal 
Published: January 2025

AbstractBackgroundPossession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer’s disease (AD). Studies investigating APOE4’s associated AD risk have largely centered on APOE4’s propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4’s role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles. However, to date, it remains unclear if APOE4 can alter pathological tau spread and if these effects are dependent on regions associated with early tau accumulation in AD.MethodTo recapitulate tau spread observed early in AD, we developed a novel human APOE mouse that expresses misfolded human tau localizing to the entorhinal cortex (EC). These mice were generated by crossing homozygous mice possessing various humanized APOE alleles to mice harboring the human MAPT P301L mutation. Human MAPT was placed under control of the neuropsin‐tTa promoter to selectively expresses misfolded tau to the EC. Both male and female mice were analyzed at various ages up until 27 months using various in‐vivo and ex‐vivo techniques to measure tau pathology and propagation, spatial memory defects, and neurodegeneration.ResultWe observed differential tau spread and neurodegeneration altered by APOE genotype in both a sex‐dependent and age‐dependent manner. Our results point predominantly to decreased tau pathology in regions associated with early AD in homozygous APOE4 mice. Analysis of the middle‐aged cohort revealed a significant decrease in tau propagation and associated atrophy to the hippocampus and lateral EC in homozygous female APOE4 mice. The observed effect on neurodegeneration and tau burden were attenuated in both male counterparts.ConclusionHere we report the generation and characterization of a novel APOE‐tau mouse model that recapitulates the region‐specific tau pathogenesis observed in early AD. Our results offer novel insights into APOE4’s role in AD by altering the sex‐dependent propagation of pathological tau along anatomically connected, vulnerable AD brain regions.