bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the Risk of Alzheimer’s Disease in Survivors of Myocardial Infarction: A Mendelian Randomization Study
Authors: Ashebir Yibeltal Arega , Zhang Yian , Shao Yongzhao 
Published: January 2025

AbstractBackgroundMyocardial infarction (MI) is a leading cause of death while those surviving MI are still at risk of developing dementias. Alzheimer’s disease (AD) is the leading cause of dementia currently without a cure or an effective prevention even in vulnerable subpopulations. Both AD and MI are common causes of disabilities and deaths in aging populations. It is of interest to investigate AD risk and possible preventive measures for AD among vulnerable aging populations including those surviving MI (survMI).MethodEmploying a two‐sample Mendelian randomization (2SMR) analysis, we assessed the causal relationship between survMI and the risk of AD, utilizing independent AD and MI genome‐wide association study (GWAS) summary datasets. Sensitivity tests, including MR‐Egger intercept test, Cochran Q‐test, and leave‐one‐out analysis, were performed to ensure robustness.ResultThe 2SMR study, utilizing 62 independent single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), revealed a decreased risk of AD associated with survMI (OR = 0.897, p = 6.03E‐11). The MR‐Egger intercept test (p = 0.405) indicated the absence of horizontal pleiotropy, and no evidence of heterogeneity was observed based on the Cochran Q‐test (p = 0.429). Some of the instrumental genetic variants, rs765549, rs11652894, rs12693302, and rs10455872 are linked to LPL, SREBF1, PDE1A, and SLC22A3 genes—targets of medicines and dietary supplements like calcium channel blockers and Omega‐3/fish oil commonly used to enhance MI survival chances.ConclusionThe 2SMR analysis indicated a significant causal association between survMI and a reduced risk of AD. This suggests that commonly‐used medications, including calcium channel blockers, and supplements like Omega‐3 products, may contribute to lowering the risk of AD. Further studies are essential to validate these findings and explore potential preventive measures for AD using combinations of medications and dietary supplements commonly employed to enhance the probability of surviving MI.
Somatic Loss of the Y Chromosome and Alzheimer’s Disease Risk
Authors: Cukier Holly N. , Palmer Ellen L. , Benchek Penelope , Wheeler Nicholas R. , Smeisek Sandra , Naj Adam C. , Haines Jonathan L. , Pericak‐Vance Margaret A , Forsberg Lars , Song Yeunjoo E. , Bush William S. 
Published: January 2025

AbstractBackgroundMosaic loss of the Y chromosome (LOY) is a somatic, age‐related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer’s Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis.MethodIn this study, we further validate the association between LOY in blood and AD via prospective analyses of 1,447 males. We defined a continuous estimate of LOY mosaicism by computing the median of the log R ratio (mLRRY) from raw intensity genotyping data. We also perform Mendelian Randomization analysis on 10,013 males across 26 US cohorts from the Alzheimer’s Disease Genetics Consortium (ADGC) dataset.ResultAge at blood draw was stratified into four bins consistent with prior literature (≤65, 66‐75, 76‐85, ≥86), and Wilcoxan rank sum tests were performed to examine the distribution of LOY by age at blood sampling. This trend of LOY increasing with age was highly significant over all samples and between all age groups. Within males with an available clinical diagnosis (n = 3117), there are significant differences between males ≤65 and all other age groups (66‐75 p = 0.00061, 76‐85 p = 7.9e‐12, ≥86 p = 5.5e‐13).To evaluate the association between LOY and risk of developing AD in follow‐up, we fit a Cox proportional hazards model associating binary LOY to years of disease‐free follow‐up within 1,447 individuals for whom blood was sampled prior to any AD diagnosis. Of these, there were 42 subsequent AD events with all others remaining controls. Overall, we find a significantly increased hazard (1.98 [1.17–6.91], p = 0.0021) in men with LOY versus those without. To account for potential biases in sample ascertainment with respect to age and case/control status, we performed Mendelian Randomization analyses of LOY. Using the Wright‐based instrument, we had a significant two‐sample Mendelian randomization effect using the Inverse Variance Weighted approach (p = 0.008).ConclusionSignificant results from these analyses provide further evidence for a role of LOY in the development of Alzheimer’s Disease.
Protein degradation impairment and synapse elimination by microglia in BSN P3866A knock‐in mouse model of tauopathy
Authors: Patel Henika , Martinez Pablo , Lopes Daniella , Jury Nur , Vanderbosch Katie , You Yanwen , Kouri Naomi , Rothberg Darren M. , Yaguchi Hiroaki , Tanaka Shinya , Wakabayashi Koichi , Yabe Ichiro , Murray Melissa E. , Reeves Cristian A Lasagna 
Published: January 2025

AbstractBackgroundTau aggregation is the major cause of several neurodegenerative tauopathies. Tau interaction with other proteins affects the formation of tau aggregates with seeding activity but less is known about its effects on tau‐seed properties. Our previous study revealed that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity in vivo. Bsndownregulation reduced tau spreading and overall pathology. Intriguingly, a parallel study associated missense mutations in BSN with tau aggregation in patients, prompting an investigation into the influence of genetic mutations in BSN on tau pathology for potential therapeutic insights.MethodWe generated a knock‐in mouse model (BSNKI) harboring the disease‐associated p.Pro3866Ala mutation in endogenous Bsn. Cognitive and motor abilities were assessed in aged heterozygous and homozygous BSNKI mice, followed by analyses of BSN and tau patterns, gliosis, and gene expression changes in their brains. Additionally, we validated our findings in a human BSN mutation carrier.ResultAt 10 months, BSNKI mice displayed motor impairments on the rotarod, and grip strength assays compared to WT mice. Their brains displayed somatic BSN and pathological tau accumulation, with the gene expression changes indicating alterations in microglia activation, protein degradation pathways, complement activation, and synapse pruning. We also observed an accumulation of pathological tau at the synapses and synapse engulfment by microglia. Histopathological analyses revealed robust microglia activation and co‐deposition of proteasomal subunits with BSN. The human BSN mutation carrier displayed inclusions of BSN and tau pathology similar to observations in the BSNKI model.ConclusionOur BSNKI mouse model, reflecting a disease‐associated BSN mutation, revealed motor impairments and pathological tau and BSN deposits, mirroring observations in BSN mutation carriers. Notably, BSN seems to play a dual role, promoting tau aggregation and sequestering protein degradation molecules, leading to tau and protein accumulation at the soma and synapse, triggering microgliosis and neuroinflammation. These findings propose BSN as a promising therapeutic target for tauopathies, underscoring the need for further exploration to elucidate underlying mechanisms and therapeutic implications.
Late‐life hemoglobin A1C is associated with postmortem neuropathology in older adults with and without diabetes
Authors: Biswas Roshni , Capuano Ana W. , Mehta Rupal I. , Bennett David A. , Arvanitakis Zoe 
Published: January 2025

AbstractBackgroundHemoglobin A1C (A1C) is a measure of long‐term glycemic control. In a previous study using a single measure of A1C, we showed that it is related to postmortem cerebrovascular pathology. Here, we use annually collected A1C data to study the relationship of A1C average and variability over time with neuropathology in a large number of older adults with and without diabetes.MethodOur study included annually collected longitudinal data on 820 older women and men (mean years of follow‐up 4.0 years, SD = 4.5) who had at least two measures of A1C and two neuropsychological evaluations, and who agreed to autopsy. We excluded those with dementia at the time of their first A1C measurements. Systematic postmortem neuropathologic evaluations documented the presence and size (macroscopic and microscopic) of brain infarcts. Modified silver stain‐based Alzheimer’s disease (AD) measures included global scores. We evaluated the association of A1C mean and variability (measured as the coefficient of variation of A1C measurements) during the study, with neuropathology, using a series of models (e.g., linear models, logistic regression, and extensions) adjusting for age at death, sex, and education.ResultParticipants (mean age‐at‐death = 90.9 [SD = 6.5] years; education = 15.8 [SD = 3.3] years;75% women) had an average of 5.7 (SD = 2.8) annually collected A1C measurements. The average person‐specific mean and coefficient of variation of A1C during the study were 6.0 (SD = 0.64) and 0.04 (SD = 0.03), respectively. Analyses showed that the mean A1C was associated with an increased odds of macroinfarcts (OR = 1.27; 95%CI:1.01‐1.59), but not microinfarcts. Notably, mean A1C was inversely associated with global AD pathology (β = ‐0.08, p‐value = 0.01). Variability in A1C was not associated with neuropathology.ConclusionUsing longitudinal A1C measures, we confirmed that A1C level is associated with cerebrovascular pathology and identified an inverse association with AD pathology. However, A1C variability over time showed no associations. Further studies are needed to understand the relationship of A1C to neuropathologies.
Behavioral studies in a new mouse model of hemochromatosis mutations and Alzheimer’s amyloidosis
Authors: Acquah Elvis , Johnstone Daniel ,   Adrienne (Lz) Milward
Published: January 2025

AbstractBackgroundBrain iron dyshomeostasis has been observed in behavioral deficits relevant to neurodegenerative diseases such as Alzheimer’s disease (AD), but it remains unclear whether it is a primary cause or an epiphenomenon of disease.MethodWe assessed the effects of brain iron dyshomeostasis on spatial cognition and cognitive flexibility using the IntelliCage system, recognition memory using novel object recognition tasks and anxiety‐like behavior using the open field and elevated plus maze tests. We investigated these phenotypes in a Hfe‐/‐xTfr2mut mouse model of brain iron dyshomeostasis alone (Irondys) or combined with an APPswe/PS1∆E9 model of Alzheimer’s Aβ amyloidosis (Aβ+Irondys), compared with APPswe/PS1∆E9 mice with Aβ amyloidosis alone (Aβ) or wildtype controls.ResultBrain iron levels in the Irondys models were ∼1.5x higher than wildtype control levels at 3 months of age, increasing to ∼1.8x or more at older ages. Brain iron dyshomeostasis alone had no effect on spatial cognition, cognitive flexibility or recognition memory. It moderately accelerated AD‐related anxiety‐like behavior in males when combined with Aβ, with Aβ+Irondys males spending less time in exposed areas of the open field arena than Aβ males at age 6 months (n = 7‐13 mice/group/sex, p˂0.05). At this age, irrespective of Aβ status, both male and female mice with brain iron dyshomeostasis also covered less distance in the elevated plus maze (n = 6‐10 mice/group/sex, p˂0.0001), while males of this group demonstrated this phenotype in the open field (n = 7‐13 mice/group/sex, p˂0.01). This iron‐related effect on locomotor activity was diminished by 9 months of age in the open field, with only the male Irondys groups covering less distance than the Aβ groups (n = 7‐13 mice/group/sex, p = 0.02). Interestingly, at 9 months of age, there was a dramatic reduction in locomotor activity of both Aβ mice and wildtype controls in the elevated plus maze, suggesting brain iron dyshomeostasis drives a natural age‐related decline in locomotor activity.ConclusionWhile there was generally no strong effect of brain iron dyshomeostasis on most of the AD‐related behavioral phenotypes investigated, there was striking impairment of locomotion, independent of AD‐related mutations and amyloidosis. This suggests movement impairment may be an earlier feature of brain iron dyshomeostasis than cognitive decline.
Specific expression of APOE in astrocytes reduces Aβ accumulation and plaque‐related pathology in a mouse model of amyloidosis
Authors: WANG NA , Doss Sydney V. , Chang Yuzhou , Tauer William , Ren Yingxue , Qi Fangfang , Bu Guojun , Liu Chia‐Chen , Wu Long‐Jun 
Published: January 2025

AbstractBackgroundAccumulation of the amyloid‐β (Aβ) peptide into amyloid plaque is one of the key pathological markers of Alzheimer’s disease (AD). Apolipoprotein E (APOE) is known to modify AD risk and has been reported to influence Aβ accumulation in the brain in an isoform‐dependent manner. ApoE can be produced by various cell types in the brain, with astrocytes being the main producer. Increasing studies show that altering apoE levels can influence Aβ plaque pathology. However, it is not fully understood how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology.MethodWe utilized mouse models expressing APOE isoforms in astrocytes and crossed them with 5xFAD mouse models of amyloidosis. We analyzed the changes to amyloid plaques and assessed the impact on cellular responses to amyloid plaques in condition of astrocytic APOE expression.ResultSpecific expression of APOE3 in astrocytes resulted in compact amyloid plaques and a large increase in plaque deposition, while the total plaque burden was reduced. Astrocytic APOE2 expression led to similar changes to amyloid plaques, but the fold change is lower comparing to that in astrocytic APOE3 models. Intriguingly, the total microglial response increased dramatically in condition of astrocytic APOE3 expression but not in condition of astrocytic APOE2 expression. Further, the ratio of plaque associated Lgals3/Iba1 is higher in condition of astrocytic APOE3 expression, indicating increased microglial activation. Additionally, astrocyte GFAP levels only increased in astrocytic APOE3 models, but not in astrocytic APOE2 models. Finally, APOE isoform effect on dystrophic neurites amount was also observed.ConclusionTogether, our study reveals an important role of astrocytic APOE on the deposition and accumulation of Aβ plaques as well as on Aβ‐associated downstream effects.
Assessing genetic overlap of Alzheimer’s disease with type 2 diabetes
Authors: Adewuyi Emmanuel O , Porter Tenielle , Verdile Giuseppe , Laws Simon M. 
Published: January 2025

AbstractBackgroundWhilst numerous studies have explored the relationship between Alzheimer’s disease (AD) and diabetes, there remains significant conflicting evidence as to their relationship. Some studies suggest an increased likelihood of developing AD in individuals with diabetes, especially type 2 diabetes (T2D) and that both diseases share pathological features. In contrast, other studies indicate that T2D is more aligned with vascular cognitive impairment and dementia and associated cerebrovascular/white matter pathology. Moreover, there is evidence showing no significant genetic correlation between the two disorders. Understanding the genetic relationship between these potentially comorbid conditions could offer insights into AD’s poorly understood biological mechanisms. This study used two complementary methods to evaluate the genetic relationship between AD and T2D. We hypothesise that both disorders are, to an extent, genetically correlated.MethodWe performed an extensive analysis of large‐scale genome‐wide association summary data using the ‘linkage disequilibrium score regression’ analysis (for global correlation) and ‘single nucleotide polymorphism (SNP) effect concordance analysis’ (SECA, for genetic overlap) methods. We performed several analyses testing our findings’ potential (partial) replications, using several GWAS data for AD (with and without the APOE region) and T2D.ResultWe found a highly significant positive genome‐wide (global) genetic correlation between AD (clinically diagnosed with proxy cases) and all T2D GWAS assessed, with or without the APOE region. We largely replicated the positive and significant results using clinically diagnosed AD GWAS. Utilising SECA, we found robust SNP overlap and strong effect concordance with low permutation p‐value and significant Fisher’s exact test—underscoring the strong association between SNP sets (and association in effect direction) for both disorders. Our SECA results were consistently significant irrespective of whether AD or T2D was dataset 1 or dataset 2. We replicated SECA’s results across clinically diagnosed AD and other T2D GWAS data (with or without the APOE region included).ConclusionOur analyses reveal a notable genetic correlation and overlap between AD and T2D, indicating shared genetic factors (shared genetic foundation) and biological pathways influencing the risk or susceptibility to both conditions.
Unraveling the dysregulation of Frizzled receptors in Alzheimer’s disease: Critical contributor for synapse loss
Authors: Basavaraju Nimisha , Kommaddi Reddy Peera 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by early synapse loss, which is further associated with deficits in memory and cognition. The loss of synapses could be mediated by dysregulation of molecular mechanisms crucial for maintaining synaptic structure and function. Among these mechanisms, the Wnt signaling pathway holds significant importance in regulating synaptic assembly. Specifically, Frizzled receptors have been identified as necessary and/or sufficient to recruit synaptic proteins at both the pre‐ and post‐synapse. Despite the pivotal role of frizzled receptors at the synapse, their contribution to synapse loss in AD remains relatively unclear. This lack of clarity persists as existing research on dysregulation of Wnt signaling in AD has predominantly focused on antagonist (Dkk1), kinase (Gsk3β), and co‐receptor (Lrp6). So, the goal of our study is to unravel how frizzled receptors are regulated and how they affect the phosphorylation and ubiquitination of β‐catenin at the synapse in AD.MethodPost nuclear supernatant and synaptosomes were isolated from brain cortex of nine‐month‐old male wild type and APP/PS1 mice. The samples were subjected to immunoblotting against Frizzled receptor 7 (Fzd7) and phosphorylation of β‐catenin. β‐catenin immunoprecipitated samples of synaptosomes were immunoblotted and probed for β‐catenin ubiquitination. Statistical comparisons between wild type and APP/PS1 group were conducted using two tailed, unpaired Mann‐Whitney U test.ResultProtein levels of Fzd7 are significantly decreased in synaptosomes of nine‐month‐old APP/PS1 mice compared to that of control mice. Decrease in the levels of receptor, Fzd7 implies an increase in β‐catenin phosphorylation and ubiquitination at the synaptosomes as a result of decreased Wnt signaling. Intriguingly, our observations reveal a significant decrease in both phosphorylation and ubiquitination of β‐catenin in synaptosomes of nine‐month‐old APP/PS1 mice.ConclusionDecreased phosphorylation and ubiquitination of β‐catenin is observed in nine‐ month‐old APP/PS1 mice compared to wild type suggesting an elevated Wnt signaling at the synapse. Our study provides novel insight into how elevated Wnt signaling could contribute to the synapse loss in AD.
How Does Increased Human Astrocyte‐Derived α‐Synuclein Affect Trophic Factor Release and Neurodegeneration in Neuron‐Astrocyte Synaptic Components?
Authors: Şengül Büşra , Dursun Erdinc , Gezen‐Ak Duygu 
Published: January 2025

AbstractBackgroundAstrocytes secrete neuromodulators, neurohormones, trophic factors, and synaptogenesis modulators. Trophic factors regulate various cellular processes including synaptic transmission. Astrocytes have critical roles in synaptic development and plasticity. They are involved in synapse formation and their absence leads to loss of synaptic connections and, neurodegeneration. Our previous study reported that α‐synuclein overexpression in human astrocytes alters the production and release of trophic factors. In the present study, we investigated the potential of astrocyte‐derived α‐synuclein increment to trigger the degeneration of synaptic connections and promote neurodegeneration by affecting the release of growth factors required for synapse formation.MethodA co‐culture system containing LUHMES cells which are human precursor neural cells, and human primary astrocyte cells was established. The plasmid carrying the human SNCA gene was transferred only to astrocytes using a lipid‐based transfection agent and then, SNCA overexpressing astrocytes were co‐cultured with neurons. We investigated whether the transfected α‐synuclein in astrocytes transffered to neurons or not by live cell imaging. The levels of synaptic proteins such as thrombospondin, synaptophysin, PSD‐95, and NGF were determined by western blot.ResultOur data showed that astrocyte‐derived α‐synuclein migrated to LUHMES cells, α‐synuclein pathology increased neuronal cytotoxicity and decreased NGF expression. We found that astrocyte‐derived α‐synuclein increased the production and release of astrocyte‐derived thrombospondin, the production of synaptophysin and PSD‐95 proteins that are all involved in synapse formation in neurons.ConclusionOur results indicate that α‐synuclein may affect synapse formation by increasing the thrombospondin levels. Evaluating this result with the increased membrane damage, we may speculate that these increments in synaptic proteins may be considered as a cellular response to reverse the damaged cell structures.