bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Surgical Mouse Model of Large Arterial Stiffening on Cognition
Authors: Baggeroer Caroline E , Pietri Peter A , Harrison Fiona E. , Jefferson Angela L. 
Published: January 2025

AbstractBackgroundIn humans, larger artery stiffening is associated with increased tau phosphorylation and neurodegeneration. However, because arterial stiffness often co‐occurs with other age‐related conditions like hypertension, atherosclerosis, and diabetes, it is nearly impossible to distill the underlying mechanisms specifically linking arterial stiffening to abnormal brain function. We leveraged a surgical mouse model of larger artery stiffening and used it concurrently with a transgenic Alzheimer’s disease (AD) mouse model of tau pathology to investigate the impact of larger artery stiffening on cognition. Large arterial stiffening typically occurs during middle age, so this model was tested in 5‐month old mice.Method5‐month old, male and female, P301S (n = 6) and wild‐type littermate controls (n = 11) underwent a carotid calcification surgery, where both carotid arteries was exposed to 0.3 mol/L CaCl2 (or saline as a control) for 20 minutes. Carotid compliance, shown as change in diameter within a cardiac cycle, was measured in vivo using M‐Mode Doppler Ultrasound imaging before and after surgery. Three weeks post‐surgery, mice underwent behavioral testing, including locomotor activity, elevated zero maze, Morris Water maze, Y‐maze, novel object recognition, and nest building.ResultCaCl2 exposure led to decreased post‐operatively compliance of the carotid artery as measured by a significantly decreased change in carotid diameter compared to saline treated mice in both left and right arteries (A. n = 8‐9; p = 0.0003. B. n = 8‐9; p = 0.015) (Figure 1). Preliminary data suggest the carotid calcification surgery impairs ability to learn the position of the escape platform in the Morris water maze in the wild type control mice (Figure 2). Data are not currently sufficiently powered to establish whether the same effect will also be observed in the P301S mice (n = 5‐6 per group WT, 3 per group P301S).ConclusionThe carotid calcification surgery significantly decreased compliance of the carotid artery in vivo and demonstrated successful stiffening of the large artery. The preliminary data suggest this reduced compliance impairs cognition, specifically spatial learning abilities, but whether the effect is greater in P301S mice is unclear. This model will further be used to investigate whether the carotid calcification surgery accelerates development of tau pathology seen in the P301S mice.
The crosstalk between insulin resistance and tau pathology
Authors: Kumar Rashi , Varshney Ritu , Gupta Sharad 
Published: January 2025

AbstractBackgroundDiabetes is a modifiable risk factor for Alzheimer’s disease, and GLUT4, an insulin‐dependent transporter, plays a crucial role in insulin‐resistant conditions and, consequently, in diabetes development. The study aimed to investigate the relationship between tau pathology and insulin resistance by quantifying GLUT4 expression and glucose concentration.MethodInitially, SH‐SY5Y cells underwent transfection with either a wild‐type tau plasmid or a mutant tau plasmid. Subsequently, insulin resistance was induced using high glucose or dexamethasone. The impact of these manipulations was assessed through a glucose uptake assay measuring cellular glucose concentration. Immunocytochemistry techniques were then applied to evaluate GLUT4 expression.ResultA significant increase in glucose concentration was observed under the latter condition. Additionally, there was a marked decrease in GLUT4 expression in neuronal cells transfected with the mutant tau plasmid, simulating tau pathology.ConclusionThe study provides evidence supporting insulin resistance as a contributing risk factor for tau pathology development, potentially leading to Alzheimer’s disease later in life. Tau aggregates may increase the likelihood of insulin resistance by impairing the insulin signaling pathway, ultimately resulting in Type 2 diabetes. The findings suggest that impaired insulin signaling in the brain could contribute to tau pathogenesis by decreasing GLUT4 expression, leading to hyperglycemia and cellular hypertrophy.
Hippocampal degeneration is associated with GFAP levels in individuals with vascular dementia independently of amyloidosis
Authors: Oliveira Markley , Bellaver Bruna , Lussier Firoza Z , Ferreira Pamela C.L. , Povala Guilherme , Leffa Douglas Teixeira , Bauer‐Negrini Guilherme , Rodrigues Matheus Scarpatto , Abbas Sarah , Zalzale Hussein , Rohden Francieli , Felix Cynthia , Soares Carolina , Saha Pampa , Ruppert Emma Patrice , Machado Vitor Hugo , da Rocha Andreia Silva , Tudorascu Dana , Benedet Andrea L. , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Hong Chang Hyung , Roh Hyun Woong , Zimmer Eduardo R. , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Son Sang Joon , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundVascular cognitive impairment/dementia (VD) is the second most prevalent cause of dementia following Alzheimer’s disease (AD). VD is characterized by the progression of white matter hyperintensity burden (WMH) and associated neurodegeneration. GFAP, a biomarker for reactive astrogliosis, is associated with Aβ pathology and mediates tau‐pathology in preclinical AD. However, the association of GFAP levels with the markers associated with VD is poorly understood.MethodWe assessed 796 participants from a research cohort (TRIAD: 355) and a memory clinic cohort (BICWALZ: 441) that were divided into four groups according to their Aβ (Aβ+/Aβ‐) and WMH status (WMH+/WMH‐). WMH values were corrected by intracranial volume, and cutoffs were determined based on the highest WMH value within 50% of the individuals with the lowest WMH rate in the CU Aβ‐ group. Biomarker mean level differences between groups were estimated via Ancova Tukey’s test, and linear regressions accounting for age, sex, and cognitive status were used to estimate the association.ResultFor TRIAD, WMH+/Aβ+ individuals exhibit higher levels of plasma GFAP when compared to all groups except WMH‐/Aβ+, with no differences in NfL levels and hippocampal volume between groups (Fig. 1A). In BICWALZ, only hippocampal volume differs between groups with lower levels observed in both WMH‐/Aβ‐ and WMH‐/Aβ+ (Fig. 1B’’). The association of GFAP and NfL was observed in all groups (Fig. 2A, 2B’). On the other hand, hippocampal degeneration was associated with higher GFAP levels in individuals with abnormal WMH and absence of Aβ burden in both cohorts (Fig. 3A: TRIAD: β = ‐0.3036; p = 0.0195; Fig. 3B’: BICWALZ: β = ‐0.1791; p = 0.0125).ConclusionOur findings suggest that astrocyte reactivity, as indicated by plasma GFAP levels, plays a significant role in the hippocampal atrophy observed in patients with vascular disease. These results suggest that therapies targeting astrocyte reactivity could potentially alleviate progressive cognitive deficits commonly found in patients with chronic vasculopathy.
Early loss of vascular‐astrocyte contact in the hippocampus in Alzheimer’s disease. Data from patients, in vitro and in vivo experimental models
Authors: Saravia Flavia Eugenia 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and in the walls of brain vessels. The hippocampus ‐ a complex brain structure that plays a key role in learning and memory ‐ has been implicated in the disease. However, there is limited data on vascular changes during the pathological degeneration of Alzheimer’s disease in this vulnerable structure, which has distinctive vascular features.MethodOur aim was to evaluate vascular changes in the hippocampus of AD patients and PDAPP‐J20 mice ‐ a model of AD ‐ and to determine the impact of Aβ40 and Aβ42 on endothelial cell activation.ResultWe found a loss of physical astrocyte‐endothelium interaction in the hippocampus of individuals with AD compared to non‐AD donors, along with reduced vessel density. Astrocyte‐endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP‐J20 mice, preceding any signs of morphological changes or blood‐brain barrier dysfunction in these mice. At later stages, PDAPP‐J20 mice showed reduced hippocampal vascular density and leakage of fluorescent tracers, indicating vascular and BBB dysfunction. In vitro studies showed that exposure to soluble Aβ40 in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be related to the observed reduction in occludin levels. Inhibition of the membrane receptor for advanced glycation endproducts (RAGE) prevented these changes in HBMEC. Additional results suggest that Aβ42 indirectly affects the endothelium by inducing astrocytic factors.ConclusionOur results from human and mouse brain samples provide evidence for the critical involvement of the hippocampal vasculature in Alzheimer’s disease.
Personality and affective predictors of compensation and implications for intervention recommendations
Authors: Namboodiri Sudev , Farias Sarah Tomaszewski , Harvey Danielle J. , Weakley Alyssa 
Published: January 2025

AbstractBackgroundCompensation has the potential to improve everyday functioning and delay or prevent conversion to dementia; thus, improvement of compensation is a desirable intervention target. In addition to cognition, research suggests personality and mood may affect compensation use. The primary aim of this study was to evaluate whether psychological factor(s) are significant predictors of compensation after accounting for cognition in a non‐demented older adult sample. A secondary aim was to examine if there were differences in outcome depending upon whether self or informant report of compensation was included in the model.MethodParticipants included 100 cognitively healthy older adults and 26 individuals with mild cognitive impairment (N = 126; age M = 76.67, SD = 6.79; education M = 15.58, SD = 3.03) who completed the Revised NEO Personality Inventory (used to assess Agreeableness, Neuroticism, Openness, Conscientiousness, and Extraversion) and self‐report measures from the National Institutes of Health (NIH) Toolbox (used to assess Sadness, Self‐efficacy, Anger, and Positive affect). A measurement of Grit was also completed. Self‐ and informant‐report from the Everyday Compensation (EComp) Scale were used as measures of compensation. Linear regression, controlling for cognition (Spanish and English Neuropsychological Assessment Scale Composite) was used to predict compensation (self or informant).ResultFor self‐reported compensation, anger was associated with more compensation independent of cognition (B = .18, t = 2.60, p = .01). For informant‐report, Openness was associated with greater compensation (B = .20, t = 2.02, p = .05).ConclusionParticipants with higher scores in Anger and Openness had increased compensation after accounting for cognitive status. A higher degree of Openness indicates a person is willing to try new things, which may result in an increased likelihood of trying compensatory strategies. While it is somewhat counterintuitive that greater negative emotion was associated with more compensation, anger is an activating and externalizing emotion which could facilitate compensation in response to worry about cognitive change. Results suggest that interventions should focus on ways to improve openness and activation to enhance compensation.
Unveiling Proteomic Signatures of Tau Pathogenesis through Label‐Free Mass Spectrometry Analysis
Authors: Zeng Xuemei , Chen Yijun , Sehrawat Anuradha , Abrahamson Eric E , Kofler Julia , Paljug William R , Ikonomovic Milos D , Karikari Thomas K 
Published: January 2025

AbstractBackgroundNeurofibrillary tangles (NFT), consisting of hyperphosphorylated tau aggregates, are one of the major pathological hallmarks of Alzheimer’s disease (AD). The burden of NFTs correlates with cognitive decline, and in vivo detection of NFT may help predict the clinical progression of AD. Mass spectrometry‐based proteomic analysis of brain regions affected by NFTs holds the potential to unveil the molecular mechanisms underlying tau pathogenesis and uncover novel diagnostic/prognostic biomarkers and therapeutic targets.MethodPost‐mortem frozen samples of inferior temporal and middle frontal cortex were collected from 9 cases with different severity of tau pathology assessed by Braak NFT stage. Proteins were fractionated into three fractions using sequential extraction with lysis buffers with different solubility strengths (TBS, Na2CO3, and Urea), trypsin‐digested, and analyzed using label‐free nano‐flow liquid chromatography‐tandem mass spectrometry (nano LC‐MS/MS). Linear mixed models were employed to assess the significance of proteins showing a differential abundance in tissues with Braak NFT stages 0‐III and IV‐VI or displaying Braak stage‐dependent solubility changes.ResultA total of 64908 peptides originating from 5475 protein groups were identified through the analysis of 18 brain tissue samples. Differential proteomic analysis revealed several proteins with significantly varied abundance in tissues with different severity of tau pathology. The most significant proteins among these include COL25A1, SNRNP70, MDK, ASPRV1, CLMN, DOCK5, HTRA1, LNPEP, SQSTM1 and Aβ peptides. Additionally, a number of proteins exhibited Braak‐stage dependent solubility change; a significant subset of these proteins, including SNRNP70, SNRPGP15, PRPF6, SNRPE, SNRPD1, SNRPB, and SNRPD3, is involved in the spliceosome‐mediated mRNA splicing.ConclusionOur study reveals numerous proteins exhibiting a significant association with tau pathology. These results align well with published findings that suggest the involvement of alternative splicing in reprogramming gene expression in the pathogenesis of AD. Further validation will be needed to assess their potential as therapeutic targets and/or diagnostic/prognostic biomarkers for AD pathologies.
Optimal Transport‐Based Transcriptomic Mapping Revealed Atypical Disease Progression Subtypes in Living Alzheimer’s Disease Patients
Authors: Huang Xiaoqing , Zhang Jie , Huang Kun , Reeves Cristian A Lasagna , Jury Nur 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post‐mortem AD brain studies. However, such atypical subtypes may not be easily identified in living patients, as obtaining brain samples are unfeasible, and NFT measurement is not accurate. In this study, we utilize the matched transcriptomic data from both brain and blood of ROSMAP cohort to identify such atypical AD groups in the blood transcriptomic data of live patients in other cohorts using transfer learning‐based approach, to uncover distinct molecular signatures and biomarkers for earlier and more accurate disease subtyping and prognosis in living AD patients.MethodThree subgroups were defined from ROSMAP cohort with the blood and brain RNA‐seq data based on the clinical information of their tauopathies and disease progression, namely, Asymptomatic AD, Low‐NFT AD, Typical AD, plus normal Control, which serves as our training dataset for a supervised transfer learning. Then, the labels were transferred to the blood RNA‐seq samples from two new cohorts, ADNI and ANMerge using optimal transport. Next, we identify the genes consistently expressed in three independent cohorts for that specific AD subtype. Lastly, the diffusion pseudo‐time analysis infers the temporal order of the gene expression patterns within each subgroups. Dominant genes with a consistent expression pattern across cohorts are considered as the signature for each subgroup, and their relevance to AD pathology is analyzed.ResultWe identified distinctive genes with consistent expression patterns across cohorts for each AD subgroup. Remarkably, our analysis also reveals the temporal gene expression dynamics differs for sex, age (late/early onset), and onset pattern (sudden/gradual) across the cohorts.ConclusionThrough a deep transfer learning‐based approach on the blood and brain transcriptomic data, we successfully identified the atypical disease progression subgroups among live AD patient cohorts in ADNI and ANMerge with promising biomarkers/gene signatures. The molecular signatures identified in this study not only enhance our comprehension of the underlying pathophysiological mechanisms but also hold promise for developing early prognosis and effective personalized treatments for AD and related tauopathies.
Investigating the effect of Area Deprivation Index on the association of APOE‐ε4 and APOE‐ε2 with Alzheimer’s disease in a Multiethnic Autopsy Cohort
Authors: Yepez‐Sisalema Geovanna , Kuchenbecker Lindsey A , Pradeep Aishwarya , Gonzalez‐Soto Rous M , Nguyen Thuy , Sotelo Katie D , Heckman Michael G. , Reddy Joseph S. , Allen Mariet , Serrano Geidy E , Beach Thomas G. , Prokop Stefan , Dickson Dennis W. , Ertekin‐Taner Nilüfer , Carrasquillo Minerva M. 
Published: January 2025

AbstractBackgroundAfrican Americans (AA) and Latin Americans (LA) are at a higher risk of developing AD compared to non‐Hispanic whites (NHW) but are traditionally underrepresented in AD research. The disproportionate risk is likely multifactorial including differences in co‐morbidities and structural and social determinants of health (SSDoH). AD risk is thought to result from multiple genetic and environmental factors, and their interactions (GxE). However, the molecular mechanisms underlying these interactions are largely unknown. The best‐established genetic risk factor for AD is APOE‐ε4, while APOE‐ε2 is protective. Environmental factors, such as living in neighborhoods with greater socioeconomic disadvantage, have been associated with greater AD neuropathology and worse cognitive function. Studying the potential modifying role of neighborhood disadvantage regarding associations of APOE‐ε4 and APOE‐ε2 with AD risk using a socioeconomic metric like the Area Deprivation Index (ADI) in a multiethnic post‐mortem cohort could offer valuable insights for precision medicine.MethodWe analyzed a post‐mortem cohort of 421 multi‐ethnic donors (NHW: N = 234, AD = 70, non‐AD = 164; LA: N = 145, AD = 102, non‐AD = 43; AA: N = 42, AD = 24, non‐AD = 18), from Mayo Clinic Florida, Banner Sun Health Research Institute, and the University of Florida Brain Banks as part of the AMP AD Diversity initiative. This study used the same neuropathological criteria to categorize AD vs. non‐AD as in the MayoRNAseq study (syn5550404). ADI from the Neighborhood Atlas® was obtained from de‐identified addresses. Associations of APOE‐ε4, APOE‐ε2, and ADI with AD risk were examined using logistic regression models adjusted for age‐at‐death, sex, and ethnic group; interactions of APOE genotype with ADI were also assessed.ResultAPOE‐ε4 and APOE‐ε2 showed a significant association with AD diagnosis (APOE‐ε4combined cohort OR = 3.23, P = 3.14E‐08; APOE‐ε2combined cohort OR = 0.30, P = 0.003). However, contrary to prior findings, our study found no association between ADI and AD diagnosis [OR = 1.023 (per each 10 unit increase in ADI), P = 0.629]. No significant interactions of ADI with APOE‐ε4 or APOE‐ε2 regarding association with AD diagnosis were identified (P = 0.083, P = 0.781).ConclusionThis is the first study evaluating the potential interaction of neighborhood disadvantage with APOE on AD risk in a multi‐ethnic autopsy cohort. However, these findings require further investigation in larger, more well‐powered cohorts for validation.
Long‐read sequencing reveals common structural variants as potential drivers of genetic rick for neurodegenerative diseases
Authors: Salazar Alex N , Tesi Niccoló , Sirvent Daniel Alvarez , Knoop Lydian , Zhang Yaran , van der Lee Sven J , Wijesekera Sanduni , Krizova Jana , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Reinders Marcel JT , Hulsman Marc , Holstege Henne 
Published: January 2025

AbstractBackgroundGenome‐Wide Association Studies (GWAS) have identified 86 SNPs associated with Alzheimer’s disease (AD). GWAS‐SNPs are markers of genetic variation in linkage disequilibrium (LD), which may drive the association with AD. One major class of genetic variation are Structural Variants (SVs), which can regulate transcription and translation of nearby genes. Here, we explored the interplay between large SVs (>50 bp) and AD‐associated SNPs.MethodWe performed long‐read whole‐genome sequencing of 214 individuals representing the extreme ends of the cognitive spectrum: N = 93 AD patients (age 67.2∓8.5), and N = 121 cognitively healthy centenarians (age 101.2∓1.8). We identified SVs using sniffles2 genome‐wide, further characterised them through (local) de novo assembly, and annotated tandem repeats (TR) and transposable elements (TE). Next, we estimated LD between SVs and 86 AD‐associated GWAS‐SNPs, Finally, we compared SNP frequencies and SV sizes between AD cases and centenarians using logistic regression models.ResultAcross all 214 individuals, we found >27,404 SVs (>50 bp), with a Minor Allele Frequency (MAF) ≥ 5%. Most SVs were TRs (63%), followed by TEs (37%). We found that 37 AD GWAS‐SNPs paired with 90 SVs in low to strong LD (R2 > 0.1), 56 of which involved SNP‐TR pairs (62%) and 34 involved SNP‐TE pairs (38%). In six AD loci, the SVs associated more strongly with AD risk than the leading GWAS‐SNP (p < 0.05). This includes ADAM10, CTSH, SLC2A4RG, CD2AP, SPI1, and IDUA, which were encompassed by complex haplotypes harbouring multiple TRs and TEs.ConclusionOur findings provide the first support for SVs as candidate‐drivers of the association between respective GWAS loci with AD risk. Hence, SVs may lead to increased effect sizes.