bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gut microbiome phytoestrogen production and its protective role in Alzheimer’s disease
Authors: Loew Ethan B , McCormick Beth , Haran John P 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), changes in intestinal microbiota and systemic inflammation are concomitant with neuroinflammation and cognitive decline. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation and immunosenescence seen in AD. Our research has demonstrated a decreased taxonomic diversity and an increased abundance of pathobionts in the gut of AD patients (Haran, mBio 2019), which is sufficient to promote amyloid and tau deposition in a mouse model (Chen, Gut 2023). It is unclear, however, if effects from the AD microbiome on the central nervous system can be mitigated. Here, we propose a protective mechanism where bacterial metabolites influence cognition via estrogen signaling.MethodWe have performed gut microbiome profiling on a cohort of 178 nursing home residents and used in vitro models to quantify the effects of AD‐associated bacteria and bacterial products on inflammation.ResultWe have identified a commensal bacterium, Adlercreutzia equolifaciens, to be depleted in our cohort of older adults with AD and further depleted in adults with progressive versus stable AD. A. equolifaciens metabolizes dietary isoflavones to produce (s)‐equol, a bacterial metabolite which binds to estrogen receptors. We treated cells expressing estrogen receptor beta, which is predominately expressed along the intestinal epithelium, with (s)‐equol and demonstrated (s)‐equol induces transcription of host genomic estrogen response genes (Vehicle normalized luciferase = 0.007, estradiol = 1.04, (s)‐equol = 1.23, p<0.0001). We have further demonstrated that treatment of intestinal epithelial cells with 17β‐estradiol induced the transcription of regulators of the innate immune response in an ERβ dependent manner (Vehicle RQ = 0.88, estradiol = 1.84, p<0.05). Finally, we have discovered that colonization with A. equolifaciens in the gut of older adults is associated with lower rates of colonization by the intestinal pathobiont Escherichia (Estimation of regression β‐coefficient = ‐1.422, p<0.05).ConclusionAdlercreutzia equolifaciens and similar phytoestrogen‐metabolizing bacteria may protect the intestinal epithelium against bacterial invasion and subsequent systemic inflammation, thereby preventing cognitive decline. Our continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system. A. equolifaciens is therefore a strong candidate as a microbiome‐based therapeutic acting along the gut‐brain axis in AD.
Association between known Alzheimer’s disease risk genetic variants and hippocampal atrophy along the Alzheimer’s disease continuum in a Korean cohort
Authors: Ahn Hyejin , Byun Min Soo , Yi Dahyun , Jung Gijung , Huang Yen‐Ning , Risacher Shannon L. , Griswold Anthony J. , Pericak‐Vance Margaret A , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Kang Koung Mi , Lee Jun‐Young , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young 
Published: January 2025

AbstractBackgroundLarge‐scale genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) from European ancestry identified many genetic variants associated with clinical diagnosis of AD dementia. However, it remains unclear whether these AD‐related variants are associated with AD biomarkers, particularly hippocampal atrophy, a well‐known neurodegeneration biomarker of AD in a Korean population. In this study, we investigated the association between known AD risk single nucleotide polymorphisms (SNPs) and hippocampal atrophy along the AD continuum in older Korean adults.MethodA total of 487 participants (258 cognitively normal olde adults [CN], 144 mild cognitive impairment [MCI], 85 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were included for analysis. All participants underwent 11C‐PiB‐PET/MRI. Hippocampal volume adjusted for intracranial volume (HVa) was obtained from 3D T1‐weighted MRI scans using FreeSurfer and used as a neurodegeneration marker of AD. Global beta‐amyloid (Aβ) deposition was calculated from PiB uptake in the global cortical region‐of‐interest using SPM12. From the genetic evidence gathered by the AD Sequencing Project (ADSP), which consists of 76 SNPs associated with AD, we selected 38 SNPs with a minor allele frequency (MAF) greater than 1% from the genotyping data imputed using the TOPMed imputation server in the KBASE cohort.ResultAmong 38 known AD‐related SNPs, three SNPs (rs6966331 in EPDR1, rs2242595 in MYO15A, and rs17125924 in FERMT2) were associated with HVa in an initial exploratory analysis (p<0.05). In a subsequent confirmatory analysis, the associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with HVa remained significant after controlling for age, sex, and APOE4 carrier status, as well as global Aβ deposition (p<0.001 and p = 0.009 for rs6966331 and rs2242595, respectively) (Table 1).ConclusionOur study identified associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with hippocampal volume in Korean older adults, and these associations were independent of cerebral Aβ deposition and APOE4 carrier status. These findings suggest that these AD‐related loci may contribute to the development of AD dementia via Aβ‐independent neurodegeneration.
CSF immune cell phenotypes and their related pathway activation differ by Alzheimers disease stage compared to normal controls
Authors: Bebek Gurkan , Zhao Ziyin , Hwang Mi‐Hyun , Bergmann Cornelia , Pillai Jagan A. 
Published: January 2025

AbstractBackgroundThere is significant interest in understanding the nature of the inflammatory response and its role in Alzheimers disease (AD) pathophysiology. Immune cell phenotypes and their key pathway activation by AD stage is unclear. We therefore evaluated immune cell phenotypes in the cerebrospinal fluid (CSF) and their transcriptional profile comparing AD‐dementia, Mild Cognitive Impairment (MCI)‐AD and normal cognition controls using transcriptomics.MethodWe characterized the gene expression profiles of immune cells in the CSF using both bulk RNA sequencing (RNAseq) and complementary single cell transcriptomics (scRNAseq). First, in a cross‐sectional cohort study, including 6 individuals with MCI‐AD meeting NIA/AA 2011 criteria and 9 amyloid negative controls with normal cognition, (mean age 68.75 years (SD 5.2), 58.8% Female), we identified significant pathways using gene set enrichment analysis (GSEA). Next, using scRNAseq analysis on2 AD‐dementia, 2 MCI‐AD and 2 normal controls we further elucidated the gene expression level changes in distinct immune cells. After clustering into immune cell types, we assessed their activation by GSEA and Gene set variation analysis (GSVA).ResultRNAseq analysis identified 47 genes that were differentially expressed between MCI‐AD and normal control samples (adj‐p‐val<0.05). GSEA identified downregulation of antigen processing, interferon signaling pathways, and neutrophil degranulation (adj‐p‐val<0.05). Next, scRNAseq, analysis defined immune cells within each sample and identified altered pathways that were in each cell type. We observed that CD4+CD8+ T cells were highly represented in AD‐dementia (17%) and MCI‐AD(14%) but not in normal controls(11%) (p<0.00001). The immune cell types that differed by disease stage between AD‐dementia and MCI‐AD were monocytes; increasing disease severity was associated with a transition from more classical monocytes to intermediate and nonclassical monocytes. The key pathways associated with monocytes were IL6 JAK STAT3 signaling, particularly STAT3, which is involved in monocyte‐to‐macrophage differentiation and the transition of classic monocytes to other subsets. Additionally, the pathways include interferon gamma (IFNg) response and TNF signaling via NF‐kB, which play important roles in activating macrophages and monocytes and promoting differentiation.ConclusionOur data show enrichment in the proportion of CD4+CD8+ T cells and pathways related to monocyte differentiation that differ across AD stage.
APOE4 Drives Liver/Brain Proteomic Shifts in Young Mice and Alters Metabolic Function Across iPSC‐Derived Hepatic and Neuronal Cells
Authors: Lysaker Colton R , Johnson Chelsea N , Drummond Vivien Csikos , Franczak Edziu M , Birky Cole , Gilmore Caleb , Thyfault John P , Geiger Paige C , Morris Jill K , Wilkins Heather M 
Published: January 2025

AbstractBackgroundAltered liver function and dysregulated metabolism are emerging risk factors for Alzheimer’s disease (AD). This includes genetic variation in apolipoprotein E (APOE), which is the strongest genetic risk determinant for AD. APOE is highly secreted by hepatocytes in the liver and astrocytes in the brain and plays a significant role in lipid homeostasis and metabolic function. Here, we sought to characterize how genetic variation in APOE influences hepatic and neuronal metabolic health.MethodMale and female APOE3 and APOE4 targeted replacement mice (Taconic Biosciences) were aged to 4 months of age on a standard chow diet before euthanasia. Liver and brain lysates were analyzed using data‐independent acquisition (DIA) proteomics. Isogenic APOE3 and APOE4 human induced pluripotent stem cells (hiPSCs) were differentiated to hepatocytes, astrocytes, and neurons and metabolic function was assessed using Seahorse XF analysis. Additional fluorescence‐based indicators were used to measure reactive oxygen species (ROS), calcium levels, and mitochondrial membrane potential.ResultAPOE4 drove widespread changes to the liver proteome in a sex‐specific manner. Young APOE4 female mice had 402 differentially expressed (DE) proteins when compared to their APOE3 counterparts. These included proteins related to lipid metabolism, mitochondrial dynamics, and mitophagy. Male mice showed far fewer DE proteins in comparison, with APOE4 male mice having 63 DE proteins in comparison to their APOE3 counterparts. Brain proteomics revealed alterations to metabolic pathways including NAD signaling. Additionally, APOE4 iPSC‐derived hepatocytes, astrocytes, and neurons displayed decreased mitochondrial function and increased mitochondrial membrane potential, ROS, and calcium levels.ConclusionThese results begin to reveal the impacts of APOE genetic variation on metabolic function across hepatic and neuronal models. However, underlying mechanistic relationships still need to be elucidated.
Exploring the Therapeutic Role of Rab8a in 4R‐Tauopathy
Authors: Parmar Mayur S 
Published: January 2025

AbstractBackgroundProgressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by abnormal aggregation and deposition of tau proteins in neurons and supporting brain cells. The underlying pathophysiology of these 4R‐tauopathy disorders remains unclear. In Alzheimer’s disease (AD), a related tauopathy, vesicle trafficking deficits, and impaired protein clearance are observed early in disease progression. Rab GTPase proteins play an important role in vesicular trafficking, endocytosis, and endosomal‐lysosomal pathways and have been implicated in Parkinson’s disease (PD) and AD pathology. In AD, the normal function of specific Rab proteins is disrupted early and may contribute to abnormal tau accumulation and neurofibrillary tangle formation. Among various Rabs GTPases, Rab8a’s role in AD pathology is explored and shown to accelerate endocytosed Aβ trafficking to the lysosomes and has expression found to decrease in PS1 mutant expressing cells. In contrast, Rab proteins, including Rab8a, and their contribution to 4R tauopathies such as PSP and CBD are little known.MethodIn the postmortem tissues from AD, PSP, and CBD, Rab8a protein expression was determined using western blot analysis. Further, human neuroglioma H4 cells were co‐transfected with wild‐type or mutant Rab8a and 4R0N or self‐aggregating mutant tau[P301L/S320F].ResultIn H4 cells, overexpression of Rab8a resulted in a marked reduction of total and phospho‐tau. The reduction in total and p‐tau was not observed with mutant (non‐functional) Rab8a overexpression. The Rab8a protein expression was found to be decreased in postmortem brain tissues (frontal cortex) from PSP and CBD compared to control tissue.ConclusionThe study demonstrates the Rab GTPase, Rab8a, expression in neuropathological tissues from 4R‐tauopathy disorders (PSP and CBD) and AD. In addition, the study provides evidence that Rab8a may regulate tau and associated pathology.
The role of microglial cells in amyloid propagation and aggregation
Authors: Andreo‐Lopez Juana , Bettinetti‐Luque Miriam , Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Da Cunha Celia , Trujillo‐Estrada Laura , Campos‐Moreno Cynthia , Leon Juan Antonio Garcia , Fatuarte‐Juli Ivan , Morales‐Cabello Mario , Nuñez‐Diaz Cristina , Martini Alessandra Cadete , Forner Stefania , Gutierrez Antonia , LaFerla Frank M , Baglietto‐Vargas David 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg‐AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process.MethodAmyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo‐3xTg‐AD mice were injected into the hippocampus of 7‐8‐month‐old 3xTg‐AD mice. They were analyzed 10 months post‐surgery for amyloid and microglia markers.ResultsOur findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg‐AD mice. Moreover, human and mice seeds differentially affect the presence of plaque‐associated microglia in 3xTg‐AD mice.ConclusionThese results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg‐AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key insight on how amyloid pathology progresses in AD.Funding: This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐928219 (D.B.V), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.
Cell‐type specific contribution to sex differences in Alzheimer’s Disease revealed using single‐cell transcriptomes
Authors: Wu Yiyang , Dumitrescu Logan C. , De Jager Philip L. , Menon Vilas , Schneider Julie A. , Bennett David A. , Hohman Timothy J. 
Published: January 2025

AbstractBackgroundTwo‐thirds of Alzheimer’s Disease (AD) cases are women, and our team has identified molecular factors that relate to disease in a sex‐specific manner. Here, we leverage single‐cell transcriptomics from dorsolateral prefrontal cortex (N = 424) from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853) to characterize sex‐specific contributors at cellular resolution.MethodSingle‐nucleic RNAseq data was generated and processed as previously described. Sex‐stratified and sex interaction analyses were performed by fitting negative binomial mixed models (‘Nebula’ R package) in relation to AD diagnosis, AD pathology, and cognitive decline. We also conducted gene set enrichment (‘fgsea’ R package) and global and neural‐specific cell‐cell communication profiling (‘CellChat’ and ‘NeuronChat’ R package). Correction for multiple comparisons was completed with the false discovery rate procedure.Result68% samples were females, and 37% were AD cases. We identified 85 sex‐specific effects that had FDR significant interaction effects and FDR significant stratified effects in one sex (31 for cognition, 28 for amyloid burden, and 27 for tangle burden). Most male‐specific effects were observed in endothelial cells, while female‐specific effects tended to be in excitatory neurons. Interestingly, among females higher ADGRG7 across all cell types related to more plaques and tangles, while in contract, in males’ neuronal expression of ADGRG7 was associated with lower tangle burden. Of the 85 sex‐specific effects, many have not been identified previously. Two signaling pathways had significant sex‐opposite gene enrichment effects including ‘TNFA_SIGNALING_VIA_NFKB’ for cross‐sectional cognition in microglia, and ‘OXIDATIVE_PHOSPHORYLATION’ for tangle burden in astrocytes and endothelial cells, with males enriched in upregulated genes and females enriched for downregulated genes. Compared to males with AD, female counterparts showed a significant reduction in global intercellular communication strength, particularly for incoming signals from inhibitory neurons and outgoing signals from excitatory neurons. Nevertheless, females with AD had more cell‐cell communication signals that were lacking in males with AD, such as THY1, GRN, VEGF, and COMPLEMENT signaling.ConclusionWe identified dozens of novel sex‐specific molecular associations and interesting cell‐cell communication pattern differences between sexes. Future mechanistic studies should connect these genes with their downstream effectors in a cell‐type specific manner.
DNA methylation associates with regional tau pathology beyond age and APOE
Authors: Goldberg David , Wadhwani Anil R , Wolk David A , Lee Eddie B , Bennett David A. , De Jager Philip L. , Schneider Julie A. , Zhou Wanding , McMillan Corey T 
Published: January 2025

AbstractBackgroundIn AD, neurofibrillary tangles (NFTs) develop earliest in the limbic system before spreading to neocortical areas. When accounting for covariates of AD pathology, such as age and APOE, there remains interindividual variation in NFT spread in the brain. We therefore used a machine‐learning approach to investigate whether age‐independent DNA methylation (DNAm) changes in brain associate with histopathological differences in AD.MethodWe analyzed DNAm data obtained using the HM450 array and preprocessed using the R package SeSAMe from dorsolateral prefrontal cortex of Religious Orders Study and Memory and Aging Project (ROSMAP; N = 707) participants. We trained age‐adjusted elastic net regression models to predict NFTs in middle frontal cortex, hippocampus, and a summary score from 5 regions (“total”) using 5‐fold cross‐validation. To determine if DNAm affords additional predictive power, we calculated the variance and the error of regression models that included age, sex, and APOE with or without DNAm from elastic net‐identified CpGs.ResultAge‐adjusted elastic net models of frontal cortex DNAm associated with total (cor = 0.25, p = 0.0033) and midfrontal (cor = 0.26, p = 0.0017), but not with hippocampal (cor = 0.08, p = 0.34) NFTs. Multiple regression models that included DNAm outperformed models that predicted using age, sex and APOE alone (+ DNAm: total: adjR2 = 0.682, rmse = 0.175; midfrontal: adjR2 = 0.594, rmse = 0.479) (‐ DNAm: total: adjR2 = 0.682, rmse = 0.175; midfrontal: adjR2 = 0.594, rmse = 0.479). Frontal cortex DNAm was least associated with hippocampal NFTs (adjR2 = 0.193, rmse = 1.20).ConclusionDNAm provides an additional mechanism to account for variance in NFTs amongst aging individuals. However, frontal cortex DNAm is more associated with frontal cortex NFTs than hippocampal NFTs. This finding suggests that region‐specific DNAm may support drivers of p‐tau spread between regions. Future research is necessary to determine whether DNAm differences across AD are causal or consequential.
Relations between language production and everyday functioning in older adults
Authors: Rosahl Melissa , Kaplan Marina , Mckniff Moira , Holmqvist Sophia L. , Chaturvedi Riya , Uwaomah Adaeze , Callahan Anna , McCourt Daniela , Pinsky Emma , Vallecorsa Giuliana , Brown Simone , Giovannetti Tania 
Published: January 2025

AbstractBackgroundSubtle changes in naturalistic language have been associated with cognitive abilities in older adults. This study explored script generation as a method for detection of mild cognitive impairment (MCI). Differences in human‐coded speech analysis of scripts were examined between MCI vs. Healthy Controls.Method79 older adults aged 65+ (n = 21 MCI, n = 58 normal cognition) completed a verbal script generation task (SGT) requiring descriptions of the following: making toast, coffee, a sandwich, etc. Scripts were scored for total time, number of words, essential and non‐essential steps, errors, and commentary words. Participants also performed neuropsychological testing and a Naturalistic Action Task (NAT), which required making meals with real objects. NAT performance was scored for total time, accomplishment steps, and errors. One‐way ANOVAs were conducted to compare MCI vs. Controls on the SGT. Spearman correlations were conducted to examine relations between the SGT and other measures (neuropsychological tests/NAT).ResultParticipants with MCI generated significantly fewer essential steps on the SGT (Kruskal Wallis Chi‐Squared = 7.61, df = 1, p < 0.001). Correlation analyses showed that participants who generated more essential steps on the SGT had better episodic memory scores (r = 0.29, p <0.01). Participants with better executive function took more time to complete the SGT (r = 0.23, p = 0.04) and generated more words on the SGT (r = 0.23, p = 0.04).SGT scores were significantly associated with NAT scores. More essential steps on the SGT were associated with fewer NAT errors (r = ‐0.27, p = 0.02). More non‐essential steps were associated with greater accomplishment of NAT steps (r = 0.30, p = 0.01) and fewer NAT errors (r = ‐0.27, p = 0.0216). Longer script time and more script words were associated with greater NAT accomplishment (script time: r = 0.25, p = 0.034). Greater total script words were associated with both greater NAT accomplishment (r = 0.35, p<.01) and fewer NAT errors (r = ‐0.23, p = 0.05).ConclusionScript generation scores significantly differentiated participants with MCI versus controls and were associated with independent measures of cognition and performance of everyday tasks. SGTs hold great promise as screening tools for cognitive decline and functional impairment. Automated scoring programs are needed to facilitate the use of script tasks in clinics and large‐scale research.