bluuebunny/crossref_metadata_2025_split huggingface dataset:
XBP‐1s transcriptional targets in the endoplasmic reticulum unfolded protein response ameliorate tauopathy
Authors: Kraemer Brian C. , Han Marina 
Published: January 2025

AbstractBackgroundProtein homeostasis (proteostasis) mechanisms fail with aging and disease, promoting toxic protein accumulation. Neurons are particularly vulnerable to proteostatic disruption leading to aging related neurodegeneration. Abnormal activation of the endoplasmic reticulum unfolded protein response (UPRER) is implicated in tauopathies, a group of neurodegenerative diseases characterized by pathological accumulation of the microtubule‐associated protein tau. Previous work showed neuronal overexpression of IRE1a branch UPRER transcription factor XBP‐1s suppresses tauopathy in C. elegans.MethodsWe conducted RNA sequencing of mRNAs to analyze the transcriptome of xbp‐1s and tau transgenic animals to identify genes required for XBP‐1s mediate protection from tauopathy.ResultsTranscriptomic analysis of XBP‐1s animals showed upregulation of the following genes with human homologs: csp‐1, F42G8.7, F41E7.6, Y19D10A.16, C01B4.6, dnj‐28, hsp‐4, ckb‐2, mct‐2, lipl‐3, and eol‐1. Surprisingly, each one of these genes is required for xbp‐1s‐mediated suppression of tauopathy, suggesting that XBP‐1s activates a broad and non‐redundant network of cellular mechanisms to reduce tau pathology. Of these, we examined the critical UPRER regulator BiP/hsp‐4, the ER resident HSP70 homolog. Hsp‐4 loss of function, but not loss of the cognate ER resident DNAJ protein dnj‐28, eliminates xbp‐1s‐mediated suppression of tauopathy. While hsp‐4 loss of function exacerbates tau‐induced behavioral deficits, tau protein level and phosphorylation are unaffected. High level overexpression of hsp‐4 exacerbates tau‐induced behavioral deficits and protein accumulation, while moderated hsp‐4 overexpression ameliorates this phenotype. Furthermore, caspases also appear to play an important role downstream of XBP‐1s: both the XBP‐1s target csp‐1 and its non‐XBP‐1s target gene family member ced‐3 are required for xbp‐1s‐mediated suppression of tauopathy.ConclusionsWe present a dataset illuminating the mechanism of xbp‐1s‐mediated suppression of tauopathy involving a suite of diverse transcriptional targets.
APOE rare missense variants in Japan
Authors: Miyashita Akinori , Hara Norikazu , Obinata Ai , Tsukie Tamao , Hasegawa Mai , Kikuchi Masataka , Kasuga Kensaku , Ikeuchi Takeshi 
Published: January 2025

AbstractBackgroundAPOE is well recognized to be the most influential susceptibility gene for Alzheimer’s disease (AD). For the wild‐type allele, e3, it is known that the e4 allele is a risk for AD, while the e2 allele is protective. Recently, genetic analyses with Caucasians have reported the critical associations between APOE rare missense variants (RMVs) and AD, and their importance has been pointed out in terms of disease pathogenesis of AD. For example, the Christchurch (rs121918393, p.R136S [CGC > AGC]) and the Jacksonville (rs199768005, p.V236E [GTG > GAG]) variants can be mentioned. Since there have been no such analyses or reports yet in East Asians, including Japanese, we designed this study.ObjectiveTo identify APOE RMVs in a Japanese population.MethodThrough the Tohoku Medical Megabank Organization (ToMMo) with a cohort of healthy Japanese community residents, APOE variant data were obtained from 3,307 subjects (1,810 females, and 1,497 males; mean age 55.9 years [standard deviation 14.1]) over 20 years old. Rare variants with amino acid substitutions were selected from them. The human genome database, Ensemble Human (GRCh38.p14), was searched to obtain the allelic frequency data of identified RMVs by populations. We also investigated the association with APOE common alleles, e2, e3, and e4, in the background of RMV carriers.ResultA total of 176 variants were identified in and around APOE in an approximately 7.2 kb genomic region in the ToMMo cohort. Of these, 14 were RMVs, including those previously reported. Four RMVs were found to be very rare, which were not found in the 1000 Genomes or gnomAD exomes/genomes databases. The 13 RMVs were inferred to be under the wild‐type allele, e3, as background.ConclusionThrough this survey, it became clear that there are RMVs of APOE that are unique to the Japanese population. In the future, we will expand the analysis to a discovery project on a scale of tens of thousands of individuals, including our subjects (n = approx. 2,500) collected so far. For the newly discovered RMVs, we plan to investigate their effects on the metabolism of amyloid beta and tau proteins in relation to AD.
Evaluation of feasibility, added value and satisfaction of remote digital self‐assessment for mild cognitive impairment in primary and specialized routine care with the app neotivCare
Authors: Düzel Emrah , Schoettler Michael , Sommer Harriet , Griebe Martin 
Published: January 2025

AbstractBackgroundTimely diagnosis of mild cognitive impairment (MCI) in Alzheimer’s disease (AD) is crucial for early interventions, but its implementation is often challenging due to the complexity and time burden of required cognitive assessments. Remote unsupervised self‐testing of cognition can potentially addres this health care challenge. We conducted the to date largest evaluation of feasibility and experienced added value of unsupervised digital remote assessment in primary and specialized health care in Germany.MethodThis is a prospective, multicentric health care research evaluation survey called “re.cogni.ze”. Its goal is to evaluate physician satisfaction with a remote digital assessment solution (neotivCare) in primary and specialized routine care in Germany. Physicians in different regions of Germany have been recommending the app to approximately 1000 patients for a 12‐week self‐assessment of cognition. Last patient out is on 31st January 2024. The primary endpoint is the evaluation of physicians’ and patients’ overall satisfaction with neotivCare in comparison to neuropsychological questionnaires / standard procedures using a Likert scale. Secondary endpoints include user‐friendliness, qualitative assessment of acceptance, and potential improvements on medical routine services.ResultThis is first large scale assessment of feasibility, satisfaction and experienced added value of remote digital self‐assessment of MCI in routine care. The data will be analysed according to prespecified endpoints after data closure on the 31st January 2024.ConclusionThe study results will provide insights into the feasibility, efficiency, and acceptance of new digital tools for MCI diagnosis in routine care. The re.cogni.ze survey will thus provide proof‐of‐concept information for the implementation of remote digital cognitive assessment apps for MCI into medical routine care.
Physiological β‐amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease
Authors: Cheng Yuan 
Published: January 2025

AbstractBackgroundTo investigate the physiological clearance of circulating Aβ by the liver and its role in the pathogenesis of Alzheimer’s disease (AD).MethodImmunostaining, near‐infrared imaging, and flow cytometry were used to explore the physiological clearance of Aβ by the liver and the impact of aging on Aβ clearance. Liver‐specific LRP‐1 knockdown and functional LRP‐1 minigene (mLRP‐1) expression in mice with AD were used to explore the effects of hepatic Aβ clearance on AD pathogenesis and treatment.ResultAβ was detected in hepatocytes of both humans and APP/PS1 mice, and Aβ40 and Aβ42 levels in the outflow blood of the liver (hepatic vein) were 13.9% and 8.9% lower than those in the inflow blood (composites of hepatic artery and portal vein), respectively, suggesting that circulating Aβ is removed when flowing through the liver. The hepatic Aβ uptake was lower in aged mice than in young mice. In addition, specific knockdown of the LRP‐1 gene in hepatocytes reduced hepatic Aβ clearance and increased Aβ levels in both plasma and interstitial fluid in the brain, as well as AD‐type pathologies and behavioral deficits in APP/PS1 mice. Furthermore, enhancing liver Aβ clearance by expressing functional mLRP‐1 in hepatocytes reduced brain Aβ deposition, ameliorated AD‐type pathologies, including neuroinflammation, neuronal loss, and tau hyperphosphorylation, and improved behavioral performance.ConclusionOur findings demonstrate that the liver physiologically clears brain‐derived Aβ, providing novel insights into the disease pathogenesis of AD and suggesting new interventional strategies.
Genome‐wide DNA methylation in early‐onset dementias brain tissue and lymphoblastoid cell lines
Authors: Comas‐Albertí Aina , Ramos‐Campoy Oscar , Fort‐Aznar Laura , Hervás‐Marín David , Borrego‐Écija Sergi , Bosch Bea , Sandoval Juan , Moreno Fermin , Fernandez‐Villullas Guadalupe , Molina Laura , Balasa Mircea , Lladó Albert , Sanchez‐Valle Raquel , Antonell Anna 
Published: January 2025

AbstractBackgroundEpigenetic mechanisms as a potential underlying pathogenic mechanism of neurodegenerative diseases have been the scope of several studies performed so far. However, there is a gap in analyzing different forms of early‐onset dementia to minimize the effect of aging and the use of Lymphoblastoid cell lines (LCLs) as a possible disease model for earlier clinical phases.MethodWe performed a genome‐wide DNA methylation analysis in 64 samples (from prefrontal cortex and lymphoblastoid cell lines) from Alzheimer’s Disease (AD) and Frontotemporal dementia (FTD) using the Illumina Infinium MethylationEPIC V2.0 array. The studied cohort included sporadic early‐onset (sEOAD, sFTD‐TP43, sFTD‐Tau) and genetic subgroups of AD (PSEN1) and FTD (MAPT, GRN, C9orf72), with n = 5 subjects/group. We analyzed the differentially methylated positions (DMPs) using the Beta regression model, with age and sex as covariates, and all p‐values adjusted by False Discovery Rate (FDR). Venn diagrams to visualize common genes between pairwise comparisons and heatmaps were performed to further explore the most important DMPs. Elastic Net logistic regression was used to obtain epigenetic diagnostic signatures. We also performed a correlation analysis of DNA methylation levels with Clariom D array gene expression data for the same cohort.ResultResults showed hypermethylation in patients’ groups as the most frequent finding in both tissues studied (Fig. 1). We identified common DMPs when comparing patients with healthy controls (CTRL) for each respective disease (Fig. 2, 3). Biological significance analysis revealed common pathways altered in AD and FTD affecting neuron development, metabolism, signal transduction and immune system pathways. These alterations were also found in LCLs, even some related to neuron development. We obtained diagnostic signatures to differentiate patients from CTRL. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs we observed mainly a positive correlation.ConclusionThis study enhances our understanding about the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in early clinical phases.
Advanced modeling of Alzheimer’s disease using human iPSC‐derived microglia and neurons carrying disease‐related mutations
Authors: Morello Berta Sanz , Shatri Elin Byman , Frandsen Sofie , Schmid Benjamin , Thirstrup Kenneth , Holst Bjørn 
Published: January 2025

AbstractBackgroundMicroglia are the primary immune cells of the brain and represent the main line of defense against brain environmental insults. In recent years, microglia have been implicated in Alzheimer’s disease (AD) pathogenesis by having interconnected yet opposing roles: beneficial as they clear amyloid beta (Aβ) and amyloid plaques, and detrimental as being responsible for synaptic and neuronal loss. These activities are tightly regulated by microglia receptors CD33 and TREM2. Microglial expression of both CD33 and TREM2 is upregulated and correlates with Aβ plaque load in the brain of AD patients, and genome‐wide association studies have associated genetic variants of CD33 and TREM2 with AD progression. Interestingly, humans carrying the polymorphic allele rs12459419(T) of CD33, which results in the loss of exon 2 in the CD33 transcript giving rise to a shorter isoform of CD33 (CD33‐D2), show higher CD33 expression in microglia and decreased Aβ deposition, lowering AD risk. In contrast, the heterozygous variant R47H TREM2 increases AD risk by four‐fold.MethodWe characterized the phagocytic and surveillance activity of human iPSC‐derived microglia carrying R47H TREM2 or Exon 2‐deleted CD33 (CD33ΔE2) in monoculture. Moreover, we analyzed how these microglia genotypes impact Aβ accumulation and neuronal integrity in a robust AD in‐vitro model represented by iPSC‐derived neurogenin‐2 (NGN2) neurons carrying the PSEN1 E280A mutation.ResultiPSC‐derived microglia carrying R47H TREM2 or CD33ΔE2 show altered phagocytic and migratory activities. When co‐cultured with NGN2 neurons carrying PSEN1 E280A, R47H TREM2 microglia and CD33ΔE2 microglia affect Aβ40 and Aβ42 levels and neuronal integrity.ConclusionInsights into how CD33ΔE2 and R47H TREM2 mutations regulate microglial activity in an AD context can help to characterize them as potential therapeutic targets to arrest AD progression.
Cerebrospinal Fluid GFAP Mediates the Association of β2‐microglobulin with Tau Pathology
Authors: Sheng Ze‐Hu , Wang Lan‐Yang , Wang Xiao‐Qin , Guo Fan , Lü Yang 
Published: January 2025

AbstractBackgroundRecent studies have demonstrated that β2 microglobulin is an important factor in β‐amyloid (Aβ) neurotoxicity and a potential target for the treatment of AD. Although β2 microglobulin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and Glial fbrillary acidic protein (GFAP) are involved in the neuroinflammatory response to promote the development of AD, their relationship in AD pathology remains to be studied.MethodA total of a11 participants with cerebrospinal fuid (CSF) and Plasma β2 microglobulin, CSF sTREM2, GFAP, and AD biomarkers(Aβ42; phosphorylated‐tau, P‐tau; and total tau, T‐tau) were included from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We assessed the associations of CSF/Plasma β2 microglobulin with sTREM2/GFAP and AD biomarkers at baseline and in longitudinal study. The mediation models were used to explore the potential mechanism of how β2 microglobulin afects AD pathology.ResultWe found that T+ and N+ groups had higher CSF β2M levels (both p < 0.001), but there was no difference between A+ and A‐ groups. Meanwhile, Since stage 1, CSF β2M levels gradually increased in stage 2 and SNAP. We also found the elevated CSF β2M level was associated with the higher levels of Aβ42 (β = 0.230, p < 0.001), P‐tau (β = 0.564, p < 0.001) and T‐tau (β = 0.603, p < 0.001). There were also positive association between baseline CSF β2M and levels of GFAP (β = 0.552, p < 0.001) and sTREM2 (β = 0.641, p < 0.001). Nevertheless, plasma β2M was not cross‐sectionally correlated with CSF AD core biomarkers, GFAP and sTREM2. Furthermore, only higher CSF β2M was longitudinally associated with slower increase of T‐tau (β = ‐0.025, p = 0.025). Results of mediation analyses showed that the association of CSF β2M with CSF P‐tau (mediating ratio = 25.4%, p < 0.001) and T‐tau (mediating ratio = 26.7%, p < 0.001) was partially mediated by CSF GFAP in total participants. In addition, the mediation effects of sTREM2 were not significant.ConclusionOur findings provide evidence to suggest that CSF β2 microglobulin is associated with tau pathology and mediated by CSF GFAP.
Gait and speech analysis for predicting progression in memory clinic: A two‐year longitudinal follow‐up
Authors: Liu Yi‐Chien , Chou Chia‐Ju , Lee Chia‐Ying 
Published: January 2025

AbstractBackgroundThe clinical progression of AD exhibits significant heterogeneity among individuals. Early identification of individuals likely to experience disease progression holds paramount importance within the context of a memory clinic. In the present study, we endeavor to analyze gait and speech data as potential predictors of early AD progression.MethodsBetween 2021 and 2023, we conducted a prospective recruitment of 99 participants from a memory clinic in Taiwan. All participants underwent comprehensive assessments, including amyloid PET scans, brain MRI scans, a battery of neuropsychological tests, and serum tests aimed at excluding reversible causes of cognitive impairment. Over a two‐year longitudinal follow‐up period, participants received diagnoses ranging from subjective cognitive decline (SCD), mild cognitive impairment (MCI), to mild dementia. Additionally, based on changes observed in the Clinical Dementia Rating Scale, Sum of Boxes (CDR‐SB) scores during the follow‐up period, participants were categorized into ‘progressor’ (CDR‐SB change≧1) and ‘non‐progressor’ groups. We collected speech and gait data through picture description tests and the Short Physical Performance Battery (SPPB). Speech data was manually transcribed and subsequently analyzed, focusing on 16 linguistic features.ResultsIn our cohort, 42.31% of individuals were categorized as progressors. The prevalence of amyloid positivity was notably higher among the progressors (84.09%) than in the non‐progressor group (29.63%). Our predictive modeling efforts involved logistic regression and the Receiver Operating Characteristic (ROC) curve analysis to forecast the progression of individuals within our dataset. Specifically, when we integrated gait speed and linguistic features as predictors, the Area Under the Curve (AUC) reached 0.8. In comparison, the AUC was 0.75 when we employed hippocampal volume as a predictor.ConclusionGait and speech data have the potential to serve as indicators of baseline cognitive status within a memory clinic setting. When combined, these datasets allow us to predict clinical progression with comparable accuracy to that achieved using neuroimaging techniques.
Sex differences in microvascular and Alzheimer’s disease‐related pathology in the medial temporal lobe: a quantitative neuropathological study
Authors: Bax Francesco , van den Berg Marteen L. , Oltmer Jan , Auger Corinne A. , Melloni Alexandra N. , Connors Theresa , Serrano‐Pozo Alberto , Frosch Matt P. , Greenberg Steven M. , Hyman Bradley T. T , van Veluw Susanne J. , Perosa Valentina 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) related pathologies (i.e., neurofibrillary tangles [NFTs], amyloid‐β plaques, and phosphorylated‐TAR‐DNA‐binding‐protein‐43 [pTDP‐43]) differ across sexes. However, the interaction between sex and cerebral small vessel disease (CSVD) (i.e., cerebral amyloid angiopathy [CAA] and arteriolosclerosis) on AD‐related pathologies has been less well characterized. The medial temporal lobe (MTL) is a crucial region in AD pathophysiology which harbors AD‐pathologies at an early disease stage and is vascularized by small vessels prone to CSVD. We therefore aimed to analyze the relationship between sex and CSVD on AD‐related pathologies in the MTL of a pathological AD cohort.MethodsThe study included autopsy cases from the Massachusetts AD Research Center. One hemisphere was formalin‐fixed, samples from pre‐defined regions (hippocampal body and entorhinal cortex) were stained for luxol fast blue with hematoxylin&eosin, amyloid‐b, At8, and pTDP‐43. Deep‐learning models (Aiforiaâ) were used to obtain quantitative measures for burden of CAA, NFTs, and pTDP‐43 inclusions. Arteriolosclerosis (grade 0‐3) was determined in vessels >20mm Ø. Mixed effect models explored age and sex (fixed terms) across regions of interest (ROIs: hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala) of the MTL on CSVD subtypes. Furthermore, interactions between sex and CSVD subtypes on AD‐related pathologies were tested. Finally, ApoE effect was evaluated in a subgroup with available genotyping.Results157 autopsy cases (80.8±12.6y, 91 females) were included, ApoE status was available in 66/157. Females had higher arteriolosclerosis severity (odds ratio for grade 2/3 = 1.56, 95% confidence interval [CI] 1.11; 2.20, p = 0.01) and lower CAA burden (b = ‐0.08, 95%CI ‐0.12; ‐0.04, p<0.001), when adjusting for age and ROIs. Moreover, females had lower burden of amyloid‐b plaques (b = ‐0.25, 95%CI ‐0.46; ‐0.04, p = 0.02) and higher density of NFTs (b = 5.16, 95%CI 1.90; 8.41, p = 0.002). Inclusion of ApoE‐status confirmed these findings with higher effect‐size, and ApoE4 genotype interacted with female sex predicting higher NFT density when adjusting for arteriolosclerosis and CAA respectively (b = 16.2, 95%CI 4.2; 28.2, p = 0.008 and b = 16.3, 95%CI 3.37; 29.22, p = 0.01). No interaction effect was found between sex and CSVD on AD‐pathology.ConclusionsIn this cohort, sex differentially affected microvascular and AD‐related pathologies in the MTL. ApoE4 genotype might act as an effect modifier of sex.
AD Pathology Spreading Detection Using Directional Motifs in Brain Connectomes
Authors: Bueichekú Elisenda , Diez Ibai , Úbeda Antonio , Kim Chan‐Mi , Jacobs Heidi I.L. , Sepulcre Jorge 
Published: January 2025

AbstractBackgroundThe accumulation of misfolded tau proteins, an Alzheimer’s disease (AD) hallmark, starts decades before the emergence of cognitive decline and clinical diagnosis. Autopsy studies support a predictable progression of tau pathology through large‐scale systems. However, less is known about the specific progression patterns. The use of connectomic metrics could enhance our understanding of the characteristics of pathology spread. We examined the spatiotemporal relationships of cortical tau accumulation using network motifs, directed graph metrics, which can reveal the underlying mechanisms governing the pathology progression routes in preclinical and clinical AD.MethodsWe used longitudinal tau‐PET data (1‐year follow‐up) from 40 adults with normal cognitive functioning and 33 adults with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3) (Table 1). We used individual and group‐level whole‐brain voxel‐wise graph theory and motifs networks analyses to investigate AD‐related tau pathology directional spreading (Figure 1a). Directional relations are established by using group‐level association matrices and by assessing differences in between‐voxels temporal relations (Time1‐Time2; FDR‐corrected, p<0.001) (Figure 1b). Then, the resulting association matrix representing the human connectome is decomposed into motif networks, which are three‐node triangular fundamental relations (i.e., exact copies of every possible motif is searched at the voxel‐level) (Figure 1c). Finally, between‐group visual comparisons of each motif reveal similarities and differences in dominant pathology spreading patterns in preclinical vs. clinical AD stages (Figure 1d).ResultsOur results support that unidirectional and serial network motifs are behind misfolded tau protein spreading in AD (Figure 2). Feed‐forward loops, cascade, and regulated mutual networks drive tau propagation in medial and lateral temporal and medial prefrontal regions early in the disease. Through the disease, spread out from one region to another (i.e., fan out and regulating mutual networks) is a common characteristic of tau progression.ConclusionOur results suggest that the progression of toxic tau through the brain systems occurs mainly in a unidirectional and serial manner. AD is considered a dysconnectivity disease. Thus, serial motifs could indicate biological relations arising on a sequential spatiotemporal scale. Future developments will examine the role of amyloid accumulation in tau progression in the context of AD.