bluuebunny/crossref_metadata_2025_split huggingface dataset:
Search for the fourth elusive haplotype of the APO E2/E3/E4 polymorphism and its potential effect on AD risk
Authors: Cheema Asma Naseer , Lawrence Elizabeth C , Zafari Narges , Fan Kang‐Hsien , Aslam Muhammad Muaaz , Acharya Vibha , Bedison Margaret A , Feingold Eleanor , Kamboh M. Ilyas 
Published: January 2025

AbstractBackgroundThe common APOE2/E3/E4 polymorphism, the strongest risk factor for Alzheimer’s disease (AD), is determined by two‐site haplotypes at codons 112 (Cys>Arg) and 158 (Arg>Cys), resulting into six genotypes. Due to strong linkage disequilibrium between the two sites, 3 of the 4 expected haplotypes (E2, E3, E4) have been observed and extensively studied in relation to AD risk. Compared to the most common haplotype of E3 (Cys112 – Arg158), E4 (Arg112 – Arg 158) and E2 (Cys112 – Cys158) haplotypes are determined by a single‐point mutation at codons 112 and 158, respectively. The fourth haplotype having mutations at both sites (Arg112 – Cys158) has been reported only as an incidental finding in five kindreds. To our knowledge, no systematic search has been done to determine its distribution in many AD and non‐AD subjects. The study aimed to search for the elusive fourth haplotype, elucidate its frequency and contextual association with AD.MethodA DNA fragment of 177bp from subjects with the APOE 2/4 genotype was subcloned with single deoxyadenosine (A) overhang on 3’ end that was amplified and ligated into 4kb PCRTM II‐TOPO vector with single 3’ deoxythymidine(T) residue then transformed into chemically competent cells (E.coli DH5aTM ‐T1R) to construct the phased haplotype clones. Plasmid DNA was extracted from successful clones and sequenced. We also confirmed the haplotype phasing by whole‐ genome sequencing.ResultWe extracted APOE genotype data on more than 14,000 AD and non‐AD subjects previously genotyped in our laboratory and identified 344 subjects with the APOE 2/4 genotype who are compound heterozygotes by carrying mutations at both sites. Thus far, subcloning followed by single‐stranded sequencing in 313 of the 344 samples have yielded phased haplotypes and the results indicate that the E4 and E2 mutations are present on opposite chromosomes. Thus, no example was observed where both the E4 and E2 mutations are on the same chromosome (Arg112 – Cys158). We are in the process of determining the haplotype phases in the remaining samples.ConclusionNo example of the elusive fourth haplotype was found in our large AD case‐control dataset, suggesting it might have a minimum effect, if any, on AD risk.
Association of Blast‐induced Hearing Loss with Progression of Alzheimer’s Disease Pathology
Authors: Kerr Nadine A , Sangaletti Rachele , Walters Winston , Rajguru Suhrud M 
Published: January 2025

AbstractBackgroundExposures to hazardous noise causes irreversible injury to the structures of the inner ear, leading to changes in hearing and balance function with strong links to age‐related cognitive impairment. While the role of noise‐induced hearing loss in long‐term health consequences, such as progression or development of Alzheimer’s Disease (AD) has been suggested, the underlying mechanisms and behavioral and cognitive outcomes or therapeutic solutions to mitigate these changes remain understudied. This study aimed to characterize the association between blast exposure, hearing loss, and the progression of AD pathology, and determine the underlying mechanisms.MethodWe employed a well‐accepted preclinical mouse model (3xTg) with a predisposition to AD pathology. Wild type (WT) and 3xTg (AD) mice were exposed to blasts in an ecologically valid oxyacetylene gas tube at 4 months of age. We compared functional outcomes (auditory brainstem responses and vestibular evoked myogenic potentials), cognitive deficits (novel object recognition, water maze), affective deficits (open field) and anxiety between WT and AD sham and blast‐exposed mice over 3 months. We also carried out immunohistochemical and Western Blot analysis for amyloid beta (Ab) amyloid fibrils, Tau, and Gasdermin‐D of the peripheral auditory system and multiple brain regions including auditory cortex and brainstem.ResultAuditory and vestibular analyses revealed a combination of temporary and permanent functional loss post‐blast combined with hair cell loss and synaptopathy. We assessed changes in cognitive function and anxiety after the induction of hearing loss in WT and AD mice. The AD, WT‐blast and AD‐blast animals had challenges with the novel object recognition. AD mice post‐blast exhibited significant increases in fecal boli present when compared to WT mice. In open field, there was a decrease in overall mean speed and total distance traveled in AD mice. Finally, there was significant elevation of Ab, Tau and Gasdermin in the cochlea as well as brainstem and cortex suggesting that pyroptosis related mechanisms play a significant role in the pathology of AD.ConclusionThese results suggest that strong association between early hearing loss and progression of AD pathology. Our novel results may inform potential biomarkers and therapeutic strategies.
Cognitive characteristics in a Uruguayan cohort of healthy subjects with high educational level in risk of development dementia and its relation with ApoE genotype
Authors: Mariani Francesca , Damian Andres , Leites Alice , Cortabarría Lucia , Bocos Laura , Santero Sofia , Contreras Valeria , Ferrando Rodolfo , García‐Fontes Margarita , Reyes Laura , Arredondo Florencia , Abin‐Carriquiry Juan Andrés , Menendez Mercedes , Amestoy Alejandra , Torheim Maren , Superchi Roberto , Suarez Ramon , Preciozzi Fabian , Uriarte Laura , Dansilio Leandro , Dansilio Sergio , Charamelo Ana , Allegri Ricardo , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sevlever Gustavo , Sosa Ana Luisa , Calandri Ismael Luis , Crivelli Lucia , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Vellila Lina Marcela , Yassuda Monica Sanches 
Published: January 2025

AbstractBackgroundApoE has been linked to individual differences in risk and resilience to neurodegeneration in normal aging. The ApoE4 genotype has been associated with an increased risk of developing late‐onset Alzheimer’s disease (age 65 and older). Within the cognitively healthy population, important differences have been reported in the distribution of ApoE4 alleles and their association with cognitive performance, especially in underrepresented groups. We describe the distribution of ApoE alleles in healthy subjects at risk of developing dementia in Uruguay, and its association with cognitive assessment and risk factors for dementia.Methodwe studied 73 subjects from the LatAm FINGERS project – Uruguayan cohort. Individuals had biobank analysis for the ApoE4 genotype, cognitive evaluation and risk factors for dementia. We compare the performance of participants in cognitive testing in relation with their ApoE allele characterization, and its relation with risk factors.Resultdemographic characteristics of study subjects are shown in Table 1. We report only one participant with E4/E4 allele combination and was exclude of analysis groups. Kruskal‐Wallis test (Table 2) revealed a significant difference in CERAD and CERAD Delayed measures between the different APOE allele combinations. We didn´t observed differences in other cognitive parameters. Also, Spearman´s Correlation showed an association between educational level, CERAD and CERAD delayed, GDS and CDR. Framingham Risk score was significantly correlated with CAIDE score.Conclusionour results suggest that the CERAD and CERAD Delayed may vary in different APOE allele combinations in normal subjects with a high educational level at risk of dementia in Uruguay. Understanding how genetic variability contributes to individual differences in cognition is important for the design of multidomain assessments and interventions, not only in subjects with cognitive impairment, but also in normal ageing in underrepresented populations.
Mosaic Loss of Chromosome Y in Peripheral Blood Cells from Whole‐Genome Sequencing and Alzheimer’s Disease in the Amish
Authors: Song Yeunjoo E. , Laux Renee A. , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Lynn Audrey , Wang Weihuan , Main Leighanne R. , Wang Ping , Liu Yining , Moore Noel C. , Prough Michael B. , Dorfsman Daniel A. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Gulyayev Alex V. , Slifer Susan H. , Adams Larry D. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Pericak‐Vance Margaret A , Scott William K. , Bush William S. , Haines Jonathan L. 
Published: January 2025

AbstractBackgroundMosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.MethodThe calling of mLOY was performed using the Mosaic Chromosomal Alterations (MoChA) pipeline, utilizing long‐range phase information to search for imbalances between maternal and paternal allelic fraction in a cell population. A loss was called when the slope of coverage over allelic deviation was ‐0.94. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. The cognitively‐impaired (CI) group combined AD, MCI and Unclear individuals and compared to the cognitively‐unimpaired (CU) group. Individuals in 3 age groups (65‐74, 75‐84, ≥85) were included. To evaluate the association between mLOY and risk of developing CI in follow‐up, we fit a Cox proportional hazards model associating mLOY to years of disease‐free follow‐up within individuals for whom blood was sampled prior to CI diagnosis.ResultAfter extensive QC, 457 males (mean age = 80.48±5.12) were included. mLOY frequency increased with age (p = 0.029): 18.75% (65‐74; n = 48), 31.86% (75‐84; n = 317) and 39.13% (85+; n = 92). A subset of 372 males were assigned to the CU (n = 202) or CI (n = 170) group and mLOY was slightly higher in the CI group (26.2% in CU vs. 34.1% in CI; p = 0.099). Within 217 males for whom blood was sampled a priori, there were 48 subsequent CI events. mLOY was associated with an increased risk of CI diagnosis with hazard ratio (HR) = 1.90 (1.03‐3.56, p = 0.04). After adjusting for the age of sampling, HR increased to 2.31 (1.23‐4.36, p = 0.009).ConclusionWe assessed the impact of mLOY in males on the risks of CI. We observed the same trend as reported in other European descent populations: mLOY increased with age and the higher sensitivity with WGS data compared with array‐based data. We found that carriers of mLOY had an increased risk of impairment.
Systemic inflammation accelerates tau propagation in an experimental model of Alzheimer’s disease
Authors: Howard Sarah , Ahmed Zeshan , Deinhardt Katrin , Teeling Jessica 
Published: January 2025

AbstractBackgroundSystemic inflammation in patients with Alzheimer’s disease (AD) has been associated with an exacerbation in cognitive decline, but the underlying mechanisms remain largely unknown. In AD, intraneuronal hyperphosphorylated tau spreads through the brain via trans‐synaptic prion‐like propagation. Evidence suggests that propagation of tau pathology is linked to neuroinflammation. Here we aim to investigate if a low‐grade systemic bacterial infection drives neuroinflammation and exacerbates the spread of tau using an experimental model of ADMethodC57BL/6 mice underwent intracerebral injection of vehicle or AT8‐positive human tau lysate, isolated from post‐mortem AD tissue. Two months post‐injection, mice were given a systemic injection of saline or a life bacterial strain. Body and spleen weight was measured to confirm infection and brain tissue was collected 4 weeks post‐infection to assess tau pathology and markers of neuroinflammation.ResultWe observed tau pathology in mice exposed to human tau lysate. Pathology in the dorsal fornix and the supramammillary nuclei was observed only in mice exposed to a bacterial infection. We also examined the inflammatory markers MHCII and CD64 and detected increased expression in mice exposed to a bacterial infection. The inflammatory response was localised to regions where pathology was observed, such as the CA3‐dentate gyrus axis.ConclusionFollowing intracerebral injection of human tau lysate, propagation of tau was induced both dorsal and ventral to the injection site. The extend of pathological tau was exaggerated by the presence of low‐grade systemic inflammation. This suggests that systemic inflammatory episodes in AD patients may induce greater propagation of tau pathology.
Effect of Music Stimulation on Network Activity of Patients with Dementia with Lewy Bodies
Authors: Chenchu Vishnu Shandilya Mungamuru , Addo‐Osafo Kwaku , Stepter Joshua , Elrayes Karen , Mohammed Aisha , Kilgore Sydney , Figueroa Katy , Vossel Keith 
Published: January 2025

AbstractBackgroundDementia exhibits abnormal network activity, including altered gamma frequency (30‐100 Hz) in Alzheimer’s disease (AD). A non‐pharmacological, non‐invasive approach to AD treatment involves stimulating sensory inputs using gamma band, with 40 Hz as the most effective in eliciting a robust EEG response. Light and sound stimulation at 40 Hz reduces AD pathology in mouse models and improves cognition in humans with AD. However, the effects of this stimulation in patients with dementia with Lewy bodies (DLB) and mild cognitive impairment (MCI) is unknown, as well as whether musical sounds can be more efficient than sounds without music.MethodIndividuals with DLB, MCI, AD, and controls participated in a music‐based brain stimulation study. Participants listened to music enhanced at 40 Hz with an overlapped 40‐Hz tone using headphones while connected to an EEG with 200‐to‐2000‐Hz sampling rate and 10‐20 placement. 40‐Hz flickering light was stimulated transiently at time intervals alone or in combination with sound stimulation. Participants underwent a 10‐minute initial assessment consisting of combinations of light/sound inputs followed by 1 hour of music and intermittent light stimulation. Power spectral density (PSD) and correlations of PSDs with different stimuli were measured.ResultIn DLB (female, mid‐50 s), sampled at 200 Hz, PSD showed a broad increase in response during gamma frequency stimulations. Light at 40 Hz (L40) resulted in increased response at 40 Hz at O1 and O2 electrodes, with a visible spike on the PSD. Music with 40‐Hz enhancement and 40‐Hz overlaid tone (M40) resulted in a strong positive correlation (SPC; Pearson correlation coefficient ≥ 0.5) at C3, C4, P3, O1, F8, T3, T4, T5, T6 and strong negative correlation (SNC; coefficient ≤ ‐0.5) at Fp1. Previously, 4 patients (1‐AD,1‐MCI,2‐controls) were sampled at 2000 Hz, which generated very low signal‐to‐noise ratio (SNR) and responses to stimulations were variable in these groups.ConclusionIn DLB, music with 40 Hz enhancement and tone increased gamma frequency response, especially in temporal regions, with strong positive correlations. Ongoing studies will determine the responses of brain oscillations to music‐based stimulations in additional participants with DLB, MCI, AD, and controls.
Peripheral metabolism informs on future cognitive decline and development of Alzheimer’s disease in population at risk
Authors: Liang Nuanyi , Nho Kwangsik , Newman John W. , Arnold Matthias , Huynh Kevin , Meikle Peter J , Borkowski Kamil , Kaddurah‐Daouk Rima ,   Alzheimer’s Gut Microbiome Project Consortium (AGMP),   the Alzheimer’s Disease Metabolomics Consortium, for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

AbstractBackgroundPeripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer’s disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g., triacylglycerol of high‐density lipoprotein). However, it is unclear if the relationship between peripheral metabolism and AD‐related markers is heterogenous among diverse populations and throughout the disease progression.MethodsUtilizing Alzheimer’s Disease Neuroimaging Initiative data, we determined whether baseline plasma GlycA can inform on cognitive and brain structural changes among sub‐populations with different diagnosis status. Furthermore, correlation analyses were performed between blood metabolomics and cerebrospinal fluid (CSF) proteomics data in sub‐populations with different diagnosis status or different mild cognitive impairment (MCI)/AD outcomes in 3 years.ResultsGlycA was elevated in AD patients compared to cognitively normal participants. Baseline GlycA level was associated with executive function decline at 3‐9 year follow‐up in participants diagnosed with late mild cognitive impairment (LMCI) at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. In addition, peripheral metabolomics signatures of CSF proteomics were well‐distinguished between cognitive normal participants and AD patients. Moreover, different peripheral‐central metabolic connection was also observed in MCI‐AD converters vs. MCI‐MCI non‐converters across 3 years follow up.ConclusionPeripheral inflammation was linked to future cognitive decline and brain structural atrophy for population at risk. In addition, peripheral metabolomics‐CSF proteomics correlation reveals distinguishing peripheral‐central connection patterns in AD patients as well as MCI participant soon to develop AD in 3 years. Findings here point to peripheral systemic inflammation and metabolic health in general as risk factors in AD development, pointing to therapeutic intervention related to periphery metabolic health for patients at risk.
Analyzing the expression of candidate genes in whole blood of autosomal dominant Alzheimer’s Disease
Authors: Comas‐Albertí Aina , Ramos‐Campoy Oscar , Pérez‐Millan Agnès , Bosch Bea , Gómez‐Núñez Alba , Puey Roger , Fernandez‐Villullas Guadalupe , Balasa Mircea , Lladó Albert , Antonell Anna , Sánchez‐Valle Raquel 
Published: January 2025

AbstractBackgroundAutosomal dominant Alzheimer’s Disease (ADAD) represents around 0.5% of all AD cases, and is caused by mutations in PSEN1, PSEN2 and APP genes. Gene expression studies can be useful for unravelling the physiopathology of AD and identifying potential biomarkers. However, most studies are focused on late‐onset AD (LOAD), and mainly on brain tissue or immune cells. Preliminary data from our group showed 9 common differentially expressed genes (DEGs) both in brain tissue and lymphoblastoid cell lines in ADAD versus healthy controls (AMMERCR1L, FMR1, FXYD5, PRR3, RNU2.1, SCARNA2, SLC35A1, TCEAL8, TMEM184B). We aim to investigate these DEGs along with 3 AD relevant genes (APP, PSEN1 and MAPT) in whole blood of ADAD with the goal to explore new potential biomarkers.MethodOur cohort (N = 69) consisted of ADAD symptomatic mutation carriers (SMC; N = 19), asymptomatic mutation carriers (AMC; N = 18) and healthy non carriers (CTRL; N = 32). RNA was extracted from whole blood and relative gene expression was determined by RT‐qPCR and ΔΔCt method. Permutation tests were used to determine the differential gene expression between groups. Additionally, a correlation analysis was performed between estimated years of onset (for AMC) or years since onset (for SMC) and relative expression.ResultDEGs were mainly down‐regulated in ADAD with respect to CTRL, except for FXYD5 and MAPT, which were up‐regulated. When comparing ADAD mutation carriers versus CTRL the significant genes were APP (p = 0.045), FXYD5 (p = 0.018), MAPT (p = 0.041), PSEN1 (p = 5e‐4), SCARNA2 (p = 0.042) and TMEM184B (p = 0.0042) (Fig. 1). Then, we compared AMC versus CTRL and SMC versus CTRL and found two DEGs in both comparisons: FXYD5 (p = 0.015; p = 0.033) and MAPT (p = 0.015; p = 0.034). In AMC group we also found these DEGs: FMR1 (p = 0.011), PRR3 (0.029), PSEN1 (p = 2e‐4), SCARNA2 (p = 0.027) and TMEM184B (p = 5e‐4) (Fig. 2). Results showed a significant negative correlation for RNU2.1 (p = 0.016) and PRR3 (p = 0.029) between relative expression and years since onset in SMC (Fig. 3).ConclusionMutation carriers show some DEGs in whole blood, even in the asymptomatic stage. FXYD5 and MAPT genes show a consistent up‐regulation in both SMC and AMC, suggesting it could be further validated as a possible genetic biomarker in whole blood of ADAD.
Neurodegenerative Changes to Subiculum Cell Type Morphology in 5xFAD Mice
Authors: Smith Zion MK , Becerra Marlene , Zepeda Nancy C , Pham Luc , Lee Darrin J , Bienkowski Michael S 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurological disorder marked by progressive cognitive decline, memory deficits, and neuronal cell loss (Knopman, 2021). A brain region significantly impacted by the progression of AD is the subiculum, a structure responsible for spatial navigation, cognitive processes, and the modulation of emotional and affective behaviors within the hippocampus (Fanselow and Dong, 2010). Although subiculum cell loss has been well‐established as an early indicator of AD (Carlesimo et al., 2015), neurodegenerative changes to cell morphology can only be observed post‐mortem and are limited by tissue histology and staining approaches that cannot completely label neuronal morphology. Using AD mouse models, G‐deleted rabies viral tracers can fluorescently label full projection neuron cell type morphology for 3D reconstruction analysis and identify neurodegenerative changes to soma and dendrites across varying disease timepoints. Understanding morphological changes during disease progression can help identify neuronal cell type susceptibility, which precedes cell death.MethodsUsing 5xFAD mice at 2 and 8 mo. timepoints, we injected G‐deleted rabies viral tracers into the medial mammillary (MM) and lateral hypothalamus (LHA) to retrogradely label MM‐ and LHA‐projecting subiculum neurons. After a 1‐week survival time, brains were extracted, sectioned into 500µm thick coronal sections, processed for SHIELD tissue clearing histology, and 3D imaged using a confocal microscope with 250nm isotropic resolution.ResultsOur findings revealed that G‐deleted rabies vectors fluorescently labeled both ‘healthy’ and ‘sick’ pyramidal neurons within the subiculum, suggesting individual neurons at different stages of neurodegeneration. ‘Sick’ subiculum neurons displayed a variety of distinct alterations in their morphology, including shrunken cell bodies caused by decreased cytoplasm around the nucleus, the emergence of swellings and thinning of dendrites, and complete dendrite collapse. Our analysis of subiculum neurons suggests a progressive timeline of morphological degeneration that precedes cell death within the subiculum.ConclusionOur findings have the potential to not only deepen our understanding of the degenerative morphological process in AD but also determine the cellular processes that precede neuronal death, which may in turn lead to developing targeted interventions that could prevent this fate.