bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracellular Tau Clearance by Immunotherapy Mediated by TREM21
Authors: Kayed Rakez , Gaikwad Sagar 
Published: January 2025

AbstractBackgroundPathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD), and more abundant in intracellular vs. extracellular compartments. However, current immunotherapies are slow and ineffective at clearing intracellular tau aggregates.MethodWe developed toxic tau conformation–specific monoclonal‐antibody‐2–loaded micelles (TTCM2‐ms) that selectively recognize disease‐relevant tau aggregates in brain tissues from patients with AD, progressive supranuclear palsy, and dementia with Lewy bodies and potently inhibit tau‐seeding activity.ResultA single intranasal dose of TTCM2‐ms effectively cleared pathological tau, increased levels of synaptic proteins, and improved cognitive functions in aged tauopathy mice. Mechanistic studies suggest that TTCM2‐ms clears intracellular, synaptic, and seed‐competent tau aggregates via tripartite motif‐containing 21 (TRIM21), an intracellular antibody receptor and E3‐ubiquitin ligase. TRIM21 is essential for TTCM2‐ms–mediated clearance of tau pathology.ConclusionOur findings suggest that intranasally administered TTCM2‐ms rapidly distributes across the brains of tauopathy mice. Further, TTCM2‐ms recognized and cleared pathological tau from the intracellular and synaptic compartments of neuronal cells via TRIM21, thus improving cognitive functions. This study provides insights into the mechanisms of an effective tau immunotherapy strategy against intracellular tau pathology in neurodegenerative tauopathies, including AD.
The relationship between sex‐steroid hormones and brain volume variation in aging
Authors: Magalhães Thamires Naela Cardoso , Jackson Trevor Bryan , Gonzales Ivan Herrejon , Bernard Jessica A 
Published: January 2025

AbstractBackgroundOlder females, particularly susceptible to Alzheimer’s disease (AD), may be affected by hormonal fluctuation during life. We aim to investigate the relationship between changes in brain volume and sex steroid hormones over time. We hypothesize that levels of sex hormones (17ß‐estradiol, progesterone, and testosterone) relate to changes in brain volume, especially in the hippocampus (HPC) and cerebellum (CB). The growing relevance of the CB in cognitive functions supports the exploration of potential associations in AD.MethodSubjects underwent structural magnetic resonance imaging (MRI) in conjunction with a series of cognitive and motor tasks. Roughly 12 months later, a subgroup of 91 participants—comprising 27 individuals in early middle age (average age 41±4.7 years; 13 females), 32 in late middle age (average age 58±4 years; 19 females), and 32 older adults (average age 72±6 years; 16 females)—underwent follow‐up MRI and task assessments (such as MoCA, digit, and symbol span). Saliva samples were collected during both visits for the quantification of sex hormones.ResultsAnalyzing longitudinal data with regression models that included all subjects, we found that baseline T and P levels were predictive of increased volumes in the bilateral cerebellar cortex and left HPC, respectively. In essence, individuals with higher levels of these basal hormones exhibited greater volumes over time. However, upon dividing the sample by sex, the result about P levels remained consistent in the female group. This suggests that, in females, higher baseline P levels continued to predict a greater volume in the left HPC (r = 0.351, p = 0.009; R2 = 0.57, p = 0.001). Upon closer examination of the groups independently, we identified positive correlations between baseline P levels and changes in volume (delta) of the left hippocampus (r = 0.441, p = 0.03) specifically in the middle‐aged group.ConclusionBoth T and P levels show a protective effect against age‐related structural changes. Ongoing analyses will explore this phenomenon further, with a focus on observing hormonal stages within the sample for clearer understanding.
Sex‐dependent APOE4 neutrophil‐microglia interactions drive cognitive impairment in Alzheimer's Disease
Authors: Butovsky Oleg 
Published: January 2025

AbstractBackgroundOne of the major outstanding questions in the field of Alzheimer’s disease (AD) research is the underlying mechanism by which APOE ε4, the strongest genetic risk factor for AD, contributes to disease pathogenesis. Current therapies targeting amyloid‐beta plaques show modest effect in non‐APOE4 male AD patients, and greatly increase the risk for amyloid‐related imaging abnormalities – edema/effusion (ARIA‐E) in APOE ε4 carriers. We made an important discovery that APOE4 neutrophil‐microglia interactions drive cognitive impairment in a sex‐dependent manner.MethodMicroglia isolated from AD brains and blood neutrophil transcriptomics of 142 patients across APOE variants in both sexes, utilizing snRNASeq and multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients. Reanalysis of an independent cohort of 422 human blood samples, implementing single cell deconvolution tools. Utilizing humanized AD mouse models, we extended these findings and addressed the mechanism by which APOE4 neutrophils suppress brain microglia.ResultWe identified neutrophils degranulation as the most affected pathways in microglia isolated from AD brains of APOE ε4 females and a new subset of neutrophils associated with cognitive impairment in APOE4 patients. This phenotype is defined by increased IL‐17 and IL‐1 co‐expressed gene modules in blood neutrophils of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL‐17+ neutrophils upregulated the immunosuppressive cytokines IL‐10 and TGFβ, and immune checkpoints including LAG‐3 and PD‐1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, we show that IL‐17F upregulated in APOE4 neutrophils interacts with microglial IL‐17RA to suppress the induction of MGnD phenotype, and that blocking this axis supported cognitive improvement in AD mice.ConclusionThese findings highlight the impact of peripheral immunity on AD pathology, provide a translational basis for precise targets for APOE ε4 carriers, and identify the biological rational for IL‐17F blockade in females with cognitive impairment. These findings link neutrophil signature to sex and APOE4 as drivers of AD and emphasize the necessity for personalized therapeutic interventions for AD.
Microglial inflammatory states in the progression of Alzheimer’s disease
Authors: Victor Matheus B 
Published: January 2025

AbstractBackgroundThe ability to profile gene expression at the single‐cell resolution offers the unprecedent opportunity to define the complex cellular heterogeneity of the brain in response to pathology. However, single‐cell transcriptomics, particularly within the context of postmortem human brain samples, only provide a static snapshot of the underlying transcriptional mechanisms driving the initiation and progression of diseases.MethodTo gain a more comprehensive picture of disease‐associated transcriptional programs, our research integrates single‐cell genomics with cellular reprogramming techniques for data‐driven mechanistic studies with human‐based cellular models of the brain. Here, I will discuss our recent effort in profiling the single‐cell transcriptome and epigenome of microglia isolated from human brains with varying degrees of Alzheimer’s disease (AD) pathology.ResultWe generated an extensive data set of over 150,000 unique microglial transcriptomes from over 400 postmortem human brains with and without AD pathology. Integrating our big data approach with targeted CRISPR‐mediated perturbations in microglia derived from induced pluripotent stem cells (iPSCs), we defined the temporal kinetics of inflammatory transcriptional programs adopted by microglia in response to AD. Through the lens of single‐cell genomics and cellular reprogramming, I will also discuss our current work investigating the pathophysiological role of hyperexcitable circuits in the etiology of neuropsychiatric symptoms of AD.ConclusionOur study provides essential insight into the progression of inflammatory states in microglia, providing a roadmap for therapeutics aimed at curbing neuroinflammation and microglia pathology associated with AD in a disease‐stage specific manner.
Correlation between FNDC5 expression and tau pathology in elderly individuals
Authors: Raony Ícaro , Lourenco Mychael V 
Published: January 2025

AbstractBackgroundPhysical exercise has been proposed as an approach to reduce the risk of Alzheimer’s disease (AD). Engaging in physical exercise triggers the shedding of the extracellular domain of fibronectin type III domain‐containing protein 5 (FNDC5), producing a circulating peptide (irisin) that promotes neuroprotection in AD mouse models. Despite recent evidence indicating that reduced FNDC5/irisin levels in brain and cerebrospinal fluid correlate with amyloid beta pathology, the impact of FNDC5/irisin on tau pathology remains uncertain. Here, we investigated the correlation between brain FNDC5 expression and key indicators of tau pathology in a cohort of elderly subjects.MethodFNDC5 expression and tau pathology were examined in the postmortem hippocampus of elderly subjects enrolled in The Aging, Dementia and Traumatic Brain Injury (TBI) Study (https://aging.brain‐map.org). FNDC5 expression data were obtained from RNA sequencing, whereas tau pathology was evaluated using the Braak neuropathological scale. Levels of pThr181‐tau and total tau were measured through Luminex assays, and AT8 (pSer202/Thr205 tau) was assessed by immunohistochemistry. Inclusion criteria included subjects (both males and females) aged over 77 years old, whereas exclusion criteria were presence of non‐AD dementia or a history of TBI diagnosis.ResultWe observed that individuals aged over 90 years old exhibit a trend for lower hippocampal expression of FNDC5 compared to those ranging from 77‐89 years old (t = 1.87; p = 0.06). There was also a trend among individuals with high tau pathology (Braak III‐VI) showing reduced FNDC5 expression compared to those with low tau pathology (Braak I‐II) (t = 1.93, p = 0.06). Accordingly, reduced FNDC5 expression was associated with higher AT8‐positive labeling (Spearman r = −0.40; p = 0.01) and pThr181‐tau levels (Pearson r = −0.30; p = 0.07), with no correlations observed with total tau levels (Pearson r = 0.27; p = 0.11).ConclusionThese results suggest that FNDC5 expression in hippocampus is reduced with tau pathology in humans, encouraging further studies to explore how physical exercise and FNDC5/irisin may influence tau pathology during aging.
Retinal neurodegeneration and synaptic loss in relations to core‐proteinopathies and cognitive scores in MCI and AD patients
Authors: Robinson Edward K , Rentsendorj Altan , Fuchs Dieu‐Trang , Vit Jean‐Philippe , Gaire Bhakta Prasad , Davis Miyah R , Jallow Ousman , Schneider Lon S. S. , Hawes Debra , Black Keith L , Koronyo Yosef , Koronyo‐Hamaoui Maya 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the foremost cause of global dementia, also characterized by retinal changes involving Aβ, hyperphosphorylated‐tau (p‐tau), neuronal degeneration, and tissue atrophy. Mitochondrial‐driven reactive oxygen species (ROS) production, linked to synaptic dysfunction, is common to various neurodegenerative conditions, including AD. Despite synaptic dysfunction being an early predictor of cognitive decline in AD, its occurrence in the AD retina is unexplored. This study examines retinal neurodegeneration and synaptic integrity in correlation with AD brain and retinal pathology.MethodUtilizing histological and mass spectrometry approaches, we assessed atrophy, early apoptosis, cell death markers, ROS levels and pre‐ and post‐synaptic markers in post‐mortem retinas from confirmed AD and mild cognitively impairment (MCI) patients compared to age‐ and sex‐matched subjects with normal cognition (NC). We applied Pearson’s (r) correlation analyses to determine the relationships between retinal tauopathy, amyloidosis, gliosis, ROS, apoptosis, and tissue atrophy severity, and their association with synaptic biomarkers. These retinal observations were then correlated with AD‐related brain parameters and cognitive scores.ResultProteomics analysis in AD patients’ retinas revealed a strong link between synaptic loss and neurodegeneration. In MCI and AD, we detected highly significant neurodegeneration (Nissl staining) in the outer nuclear layer (ONL; 28%; 23%), inner nuclear layer (INL; 38%; 21%), and ganglion cell layer (GCL; 54%; 52%), accompanied by increased ROS levels (1.9; 2.2‐fold; by DHE staining) respectively, compared to NC. Marked pre‐ (Synaptophysin: 56%; 77%) and post‐ (PSD95: 44%; 66%) synaptic losses were detected in the inner and outer plexiform layers of MCI and AD patients, along with strong negative correlations with accumulation of retinal pSer396‐tau, Aβ42 and gliosis. The retinas of these patients also exhibited significant increases in early apoptotic markers. Remarkably, retinal synaptic loss and neurodegeneration had a strong negative correlation with severity of cognitive impairment, BRAAK stage, and ABC score.ConclusionOur study reveals pronounced retinal neurodegeneration at pSer396‐tau and Aβ42 accumulation sites, coupled with increased retinal oxidative stress in MCI and AD patients. Elevated retinal ROS and pre‐apoptotic cells may contribute to synaptic loss and neuronal death. These findings suggest that retinal synaptic loss and neurodegeneration may predict AD status.
Genetics of Dementia with Lewy Bodies in a Chinese Population
Authors: Shen Lu , Hao Xiaoli , Xiao Xuewen , Yang Qijie , Jiao Bin 
Published: January 2025

AbstractBackgroundGenetics plays an important role in dementia with Lewy bodies (DLB) and remains poorly understood. Previous research has identified several genes associated with DLB, including APOE, GBA, SNCA, BIN1, TMEM175, PLCG2, and CNTN1. To date, genetic studies on DLB have focused on Caucasian population. The gaps in DLB genetic study on East Asian populations need to be filled. Therefore, we conducted a comprehensive genome‐wide association study (GWAS) to identify genetic risk factors for DLB in China.MethodWe performed whole‐genome sequencing on a cohort of 143 patients with DLB and 2007 healthy controls. Common variant‐based association analysis was conducted using PLINK 1.9, while gene‐based association tests for rare variants were performed using the sequence kernel association test‐optimal. Adjustments were made for gender, age, and principal components. Additionally, PLINK 1.9 was used to test variants associated with the onset age of DLB.ResultOur results confirmed previously reported associations with common variants to a certain extent, particularly the APOE gene (rs429358, p = 1.71 × 10–10). No rare‐damaging variants were significantly associated with DLB in our cohort. In the rare‐missense‐variant groups, the combined effect for USP13 gene showed suggestive association with DLB at p‐value < 1 × 10−4 (p = 7.75 × 10‐5). The protein encoded by the USP13 gene has been considered a major contributing factor to the presence of Lewy bodies based on previous research. No variants were associated with the onset age of DLB.ConclusionDespite the small sample size for a genome‐wide association study, we present the first comprehensive study in dementia with Lewy bodies in China so far. These data show that common genetic variability has a role in the disease. Further replication study of USP13 gene will be important.
The role of immune system associated genes in patients with Alzheimer’s disease: A large case‐control study in the Chinese population
Authors: Xiao Xuewen , Jiao Bin , Yao Rui , Liao Xinxin , Li Jincheng , Tang Beisha , Shen Lu 
Published: January 2025

AbstractBackgroundVarious studies indicated that the immune system is a cardinal feature of Alzheimer’s disease (AD), which can either ameliorate or exacerbate AD neuropathogenesis. Nevertheless, the associations between genes involved in the immune system and AD remain unclear.MethodTo systematically evaluate the associations of these genes with AD, we investigated 370 genes implicated in the immune system based on previous studies selected using the PubMed database. Our study recruited 1511 AD patients and 2001 cognitively normal controls. 370 genes were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)‐based association test was performed by PLINK 1.9, and gene‐based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test‐Optimal (SKAT‐O test) by combining rare variants between AD patients and cognitively normal controls. Rare variants were further categorized as followings: rare damaging variants (MAF <0.01, LoF or ReVe >0.7), rare damaging missense variants (MAF <0.01, ReVe >0.7), rare LoF variants (MAF <0.01, LoF), and rare missense variants (MAF <0.01, missense). Age, sex, and APOE ε4 status were adjusted in our study.ResultAfter quality control, 73,885 common variants were left. A common variant, MGMT rs147073440, was suggestively associated with AD risk after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {adjusted P = 1.62 × 10‐6, odds ratio (OR) [95% confidence interval (CI)] = 2.726 (1.809‐4.106)}. 250 genes with rare damaging variants were analyzed in our study. The gene‐based association analysis revealed that the rare damaging variants in the RAB37 and EPCAM genes were nominally associated with AD (p <0.004).ConclusionThis study suggested that MGMT rs147073440 and rare damaging variants in RAB37 and EPCAM may be implicated in AD pathogenesis.
Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American Ancestries using AI/ML approaches
Authors: Cheng Feixiong , Hou Yuan , Zhang Pengyue , Fan Fan , Haines Jonathan L. , Pieper Andrew A. , McReynolds Cindy , Hammock Bruce D. , Leverenz James B , Cummings Jeffrey L. 
Published: January 2025

AbstractBackgroundAlthough high‐throughput DNA/RNA sequencing technologies have generated massive genetic and genomic data in human disease, translation of these findings into new patient treatment has not materialized by lack of effective approaches, such as Artificial Intelligence (AL) and Machine Learning (ML) tools.MethodTo address this problem, we have used AI/ML approaches, Mendelian randomization (MR), and large patient’s genetic and functional genomic data to evaluate druggable targets using Alzheimer’s disease (AD) as a prototypical example. We utilized the genomic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets across five human brain regions from three biobanks. We tested the outcome of Mendelian randomization across genome‐wide association studies (GWAS) datasets of European‐American (EA) and African‐American (AA) ancestries, with 275,540 AD cases and 1.55 million controls. We searched repurposable drugs using AI‐assistant drugome‐wide association studies from ∼80 million electronic health records.ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs. Among 6 AA‐specific targets, TRPV3 is a potent drug target and replicated in AA‐specific eQTL data from the Metabrain cohort. We pinpointed that an anti‐inflammatory AD target of epoxide hydrolase 2 (EPHX2): (1) a pQTL lead SNP rs2741342 (PGWAS = 5.72 × 10‐13; PpQTL = 1.19 × 10‐16) located in an enhancer of EPHX2; and (2) a protein‐coding variant of rs751141 (p.Arg287Gln) was associated with reduced EPHX2 protein expression (PpQTL = 5.50 × 10‐16) from the AD knowledge portal. We demonstrated that TPPU (a nanomolar‐EPHX2 inhibitor) blocked deterioration in hippocampal‐dependent cognitive ability in a TgF344‐AD rat model and EC5026 (a first‐in‐class, picomolar EPHX2 inhibitor) improves cognition in a 5xFAD mouse model. We identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment patients. We found that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69–0.80) and amlodipine (HR = 0.91, 95%CI 0.88–0.94) were significantly associated with reduced progression to AD.ConclusionCombining genetics and real‐world patient data identifies ancestry‐specific therapeutic targets and medicines for AD. Further functional and clinical validation of candidate targets and drugs in ethnically diverse population are warranted.
Evolutionary Theory and Machine Learning: New Inroads Into Sex‐specific AD Susceptibility Genes and Pathways Significantly Improve Risk Prediction
Authors: Al‐Ramahi Ismael , Asmussen Jenn , Botas Juan , Katsonis Panagiotis , Lagiesetty Yashwanth , Lee Kwanghyuk Danny , Nazem Fatemeh , Samieinasab Maryam , Wang Chen , Wilhelm Kevin , Lichtarge Olivier 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) incidence is almost double in female than male, suggesting sex‐specific AD risk genes remain unknown.MethodWe designed a statistical physics approach that exploits freely available but massive evolutionary and phylogenetic coupling data on sequence variation and speciation. These couplings lead to quantifiable values for the selection pressure exerted on the genes within a population. We may then compare a gene’s influence in sequenced cases vs controls cohorts and test the hypothesis that significant deviations identify genes linked to disease risk.ResultIn 4768 AD cases and 4689 healthy controls (HC), we discovered 122 genes under greater selection pressure (q < 0.01). These genes overlapped (p = 3.10‐5) and interacted (z = 7.16) with AD GWAS genes. They also interacted mutually (n = 57, p = 0.0019) and with AD‐related processes (p = 1.0‐16). More than 50% of the genes exhibited dysregulation in AD brains in snRNAseq analysis, suggesting participation in pathogenic or protective processes in AD. Furthermore, expression of these genes correlated with increased or decreased deposition of plaques and tangles in patient brains. Moreover, the candidates are enriched in modifiers of neurodegeneration in Drosophila: knockdown or overexpression of 64 genes ameliorated or worsened age‐dependent neuronal dysfunction (p<0.05). Robustness to down‐sampling allowed to analyze smaller, sex‐separated cohorts. We identified 82 genes in males and 69 genes in females (15 genes overlapped, p < 10‐53), indicating shared as well as sex‐specific AD mechanisms. The male and the female genes overlapped (p = 6.5‐6 and 1.5‐4) and interacted (z = 5.63 and 6.18) with the AD genes. Remarkably, using these gene sets as features for predicting AD risk in separate training and testing cohorts successfully differentiated between AD cases and controls with very high accuracy, even when blinded to APOE genotype. Notably, we predicted the risk with AUCs of 0.83 with APOE, 0.83, and 0.82 in combined, males, and females, respectively.ConclusionA new statistical physics approach discovered male and female AD genes, predicting AD risk with very high accuracy. These results identify further genetic differences leading to AD in males and females, and show the power of quantitative phylogenetics to probe complex human diseases.