bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive Modeling of the Mnemonic Similarity Task predicts Alzheimer’s disease biomarker status in cognitively unimpaired older adults
Authors: Vanderlip Casey R , Lee Michael D , Stark Craig E.L. 
Published: January 2025

AbstractBackgroundAD related pathologies, such as beta‐amyloid (Aβ) and phosphorylated tau (pTau), are evident decades before any noticeable decline in memory occurs. Identifying individuals during this asymptomatic phase is crucial for timely intervention. The Mnemonic Similarity Task (MST), a modified recognition memory task, is especially relevant for early AD screening, as it assesses hippocampal integrity, a region affected (both directly and indirectly) early in the progression of the disease. Further, strong inferences on the underlying cognitive mechanisms that support performance on this task can be made using Bayesian cognitive modeling. Here, we aimed to determine the efficacy of the MST, combined with cognitive modeling, at predicting AD biomarker status during this preclinical stage.MethodUsing data from a prior study (Trelle et. al, 2021), 133 cognitively unimpaired older adults (age = 68.8±5.8, 63% female) were administered the MST and underwent a lumbar puncture to quantify AD biomarkers. All had a Clinical Dementia Rating of zero and normal neuropsychological test performance. Previously derived Aβ42, Aβ40, and p‐tau181 levels were used in the present analyses. Here, both traditional performance scores and cognitive modeling using multinomial processing trees was applied to each participants MST data using Bayesian approaches. We applied logistic regressions using both traditional metrics (“REC” and “LDI”) and model‐based metrics to predict Aβ and pTau status, assessing model efficacy via ROC analyses.ResultMST traditional metrics modestly predicted Aβ status (AUC = 0.64, p = 0.036). However, model‐based metrics were able to predict Aβ status at a higher level (AUC = 0.73, p = 0.020). We next assessed whether MST performance could predict pTau status. Our findings indicate that traditional metrics could not successfully predict pTau status (AUC = 0.50, p = 0.908). Conversely, model‐based metrics reliably predicted pTau status (AUC = 0.71, p = 0.037). Together, these results demonstrate that cognitive modeling of the MST can detect individuals with elevated AD biomarker status prior to cognitive decline.ConclusionThis work establishes the clinical utility of the MST as a screening tool for identifying older adults during the asymptomatic phase of AD which may reflect the optimal window for therapeutic intervention.
Using disease‐selective cell lines to investigate tau strain biology
Authors: Holec Sara A. M. , Brown Christine K. , Frost Matthew P. , Woerman Amanda L. 
Published: January 2025

AbstractBackgroundIn tauopathies, the protein tau misfolds into a b‐sheet conformation that self‐templates and spreads throughout the brain causing progressive degeneration. Biological and structural data have shown that the shape, or strain, that tau adopts when it misfolds determines which disease a patient will develop. We previously used HEK293T cells expressing TauRD‐YFP to show that tau strain formation is isoform‐specific. However, the field remains unable to differentiate between strains using the same isoforms, which is a critical requirement for the successful development of strain‐specific diagnostics. In this work, we hypothesize that single point mutations can be used to disrupt the misfolded tau conformations in a disease‐specific manner, enabling differentiation between tauopathies.MethodWe built a panel of HEK293T cells expressing several disease‐linked and novel mutations in 4R tau, which we selected based on mutagenesis modeling aimed at selectively inhibiting replication of tau prions isolated from either corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) patient samples. Infection conditions in the cell lines were optimized for a 384‐well plate using tau prions isolated from Tg(MAPT*P301S+/+) and non‐transgenic B6/J mice before testing human patient samples. Cells were imaged using the LionheartFX and infection was determined using custom algorithms developed in Gen5 software.ResultSamples isolated from control mice do not cause aggregation in the cell lines tested. By comparison, tau prions isolated from Tg(MAPT*P301S+/+) mice cause aggregation in some cells, but other point mutations inhibited tau prion replication. Intriguingly, the same mutations inhibited replication of tau prions isolated from PSP patient samples, but not CBD samples. Notably, within this targeted region of the protein, the cryo‐EM structures of tau fibrils in PSP patients and Tg(MAPT*P301S+/+) mice show some homology.ConclusionWe have developed two cell lines that selectively replicate tau prions isolated from CBD patient samples. To our knowledge, this is the first assay capable of differentiating between two different 4R tau prion strains, representing a significant advancement towards the development of disease‐specific diagnostic tools.
Development of a novel swine model carrying humanized APP and PSEN1
Authors: Yoon Junchul , Monarch Kaylynn , Kiesewetter Emily , Rodriguez‐Lukey Katherine , Koh Sehwon , Uh Kyungjun , Prather Randall S , Jarome Tim , Allen Tim , Lee Kiho S 
Published: January 2025

AbstractBackgroundPreclinical animal models are essential for the development of effective treatments. For instance, the 5xFAD mouse model successfully represents the pathophysiology of Alzheimer’s disease (AD). Expression of humanized APP (K670N/M671L ‐ Swedish, I716V ‐ Florida, V717I ‐ London) and PSEN1 (M146L and L286V), found in early onset AD patients, induces the production of amyloid‐β 42 (Aβ42) and amyloid deposition, gliosis, and progressive neuronal loss. While these mouse models are necessary to identify mechanisms of the disease progression, translating the findings by using large animal models such as pigs allows us to explore treatments under clinical conditions, and therefore, improve the success of clinical trial outcomes. For example, the gray‐to‐white matter ratio and the complexity of the distribution of crossing fibers in the pig brain is more similar to humans than are rodents.MethodPhenotypes of previous swine models carrying humanized APP and PSEN1 to mimic the 5xFAD mouse model did not align with the mouse model, presumably due to differences in aging rates or variation in the expression level of the genes. To accelerate the impact of the humanized APP and PSEN1, we first inactivated endogenous porcine APP and PSEN1 genes by using the CRISPR/Cas9 system in fetal fibroblast cells. Subsequently, constructs designed to express human APP and PSEN1 under the control of the neuron specific Thy1 promoter were transfected into the cells. Cells carrying the humanized APP and PSEN1 genes and the cells were used for somatic cell nuclear transfer to produce AD swine model.ResultThirteen piglets were born from a single pregnant sow and the genotyping of the piglets indicated that the piglets carried inactivated porcine APP and PSEN1 and carry humanized APP/PSEN1 as expected. Immunohistochemistry on the brain of the newborn AD piglets revealed an elevated abundance of Aβ42 compared to the wild type.ConclusionProduction of the novel AD swine model will offer a new pre‐clinical animal resource to expand our understanding of Alzheimer’s disease pathogenesis and develop effective treatments against the disease.
Single Nucleus RNA Sequencing Reveals Interaction Between Microglia and Endothelial Cells in Mixed Alzheimer’s Disease and Vascular Pathology
Authors: Olayinka Oluwatosin A , O'Neill Nicholas K , Empawi Jenny A , Bock Payton , Hu Junming , Wong Melissa , Stein Thor D. , Wolozin Benjamin , Zhang Xiaoling , Farrer Lindsay A. 
Published: January 2025

AbstractBackgroundSingle‐nucleus RNA sequencing (snRNAseq) allows for the dissection of the cell type‐specific transcriptional profiles of tissue specimens. In this study, we compared gene expression in multiple brain cell types in brain tissue from Alzheimer disease (AD) cases with no or other co‐existing pathologies including Lewy body disease (LBD) and vascular disease (VaD).MethodWe evaluated differential gene expression measured from single nucleus RNA sequencing (snRNAseq) data generated from the hippocampus region tissue donated by 11 BU ADRC participants with neuropathologically confirmed AD with or without a co‐existing pathology (AD‐only = 3, AD+VaD = 6, AD+LBD = 2). Cell types were identified using both the singleR package and manual annotation. Expression of 19,893 genes was compared between samples with AD+VaD pathology and the other AD groups for each identified cell type. Gene co‐expression modules were identified using weighted gene co‐expression network analysis (WGCNA) applied to a partially overlapping group of 174 bulk RNAseq samples (AD‐only = 73, AD+VaD = 43, AD+LBD = 54, AD+other pathology = 4). Modules enriched in differentially expressed genes (DEGs) were identified using Fisher’s exact tests. The overlap between DEGs and co‐expression modules was used for quantitative gene set analysis. Replication of findings was performed on an independent cohort of 393 ROSMAP dorsolateral prefrontal cortex (DLPFC) snRNAseq samples.ResultCompared to other AD samples, AD+VaD subjects showed decreased expression of a specific set of genes related to immune activation in microglia (t = ‐2.67, p = 0.027). The expression these genes were negatively associated with that of microglial receptors P2RY12 and CX3CR1 (r = ‐0.87, p = 1.95 × 10‐4). We similarly observed a decrease in genes that negatively regulate angiogenesis in endothelial cells (t = ‐4.84, p = 1.48 × 10‐3). An association between the expression of the microglial activation and the endothelial anti‐angiogenesis gene set was found globally within the hippocampus snRNAseq data (r = 0.68, p = 1.59 × 10‐2) and was replicated in the ROSMAP DLPFC snRNAseq independent data set (r ‐0.60, p = 5.18 × 10‐39).ConclusionWe identified genes that are differentially expressed in endothelial cells and microglia in hippocampus from persons with AD+VaD compared to other AD diagnoses. These patterns suggest that AD+VaD cases have reduced microglial activation and increased angiogenesis in the brain.
Clinical Symptoms and Risk Factors in Older Adults with Limbic‐Predominant Age‐Related TDP‐43 Neuropathology in the Context of Mixed Dementia
Authors: Scott Imogene M , Alkhodair Yara , Weber‐Adrian Danielle , MacKenzie Ian R , Hsiung Ging‐Yuek Robin 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a pathological process diagnosed at autopsy, involving deposition of TDP‐43 in the medial temporal lobes. The name LATE‐NC was recently proposed to represent the pathological process, while “LATE” has been suggested to represent the clinical syndrome. However, there are currently no available criteria to diagnose this syndrome during life, and the clinical phenotype is not well understood.MethodA sample of autopsy cases (n = 39) from the University of British Columbia Hospital with moderate to severe Alzheimer and/or Lewy Body pathology, with and without LATE‐NC, underwent chart review. 19 individuals with LATE‐NC pathology (LATE+) were age‐matched to 20 controls (LATE‐) by age and by degree of Alzheimer and Lewy Body pathology. Clinical characteristics including ages at symptom onset, diagnosis and death; cognitive test scores; medical history and functional status were extracted from the clinical charts, and compared using the t‐test and χ2 statistics.ResultIn the two groups, mean age at death was 80.7 years (LATE+) and 79.7 years (LATE‐). Age at onset (66.4 versus 68.4 years) and disease duration (11.9 versus 11.2 years) were not significantly different. Years of education (14.9 versus 13.3, p = 0.03), and prior history of head injury (33.3% vs 5.3%, p = 0.04) were both significantly higher in the LATE+ group. There was a trend towards a higher prevalence of mood symptoms in the LATE+ group (55.6% versus 36.8%), and fewer psychotic symptoms (10.5% versus 36.8%), however these differences were not statistically significant. There were no significant differences in cognitive domains affected across the disease course, or baseline cognitive test scores.ConclusionIn this study, head injury and greater years of education were identified as possible risk factors for LATE‐NC. There were differences in the burden of neuropsychiatric symptoms between the two groups which require further investigation. However, the presence of LATE‐NC did not appear to accelerate disease progression, suggesting its clinical impact is small relative to the impact of severe Alzheimer or Lewy Body pathology. Additional study including those with little or no concomitant pathology may help to elucidate the clinical phenotype further.
Effects of ketogenic diet on metabolic and cognitive‐behavioral outcomes in a mouse model of cerebral amyloid angiopathy
Authors: Pulido‐Correa Victoria , Vogel Chana , Rosenberg Lauren , Echeverria Bianca , Uribe Iliana , Hernandez Ariana , Robison Lisa S 
Published: January 2025

AbstractBackgroundCerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid protein in the cerebral vasculature, is highly prevalent in Alzheimer’s disease (AD) patients and, on its own, increases the risk of hemorrhagic stroke, cognitive impairment, and dementia. Currently, there are no effective ways to treat or prevent CAA. Ketogenic diet (KD), characterized by high‐fat, low‐carbohydrate, and moderate amounts of protein consumption, has gained considerable attention in recent years for its potential therapeutic use in patients with neurodegenerative diseases, including Alzheimer’s disease. Studies in AD rodent models have found that KD and/or ketogenic supplements attenuate cognitive‐behavioral impairments, neuroinflammation, and oxidative stress, reduce the accumulation of Aβ plaques, and enhance synaptic plasticity. However, it is unknown whether KD can similarly benefit individuals with CAA. This study, therefore, aimed to examine the potential therapeutic effects of KD in a transgenic mouse model of CAA.MethodMale Tg‐SwDI mice underwent a four‐month dietary intervention with either a standard rodent chow (macronutrient breakdown: 14.4% fat, 26.1% protein, and 59.5% carbohydrates) or ketogenic diet (macronutrient breakdown: 93.4% fat, 4.7% protein, and 1.8% carbohydrates) starting at ∼3.5 months of age. Body weight, caloric intake, and fluid consumption were assessed twice weekly throughout the duration of the experiment. Three months after diet initiation, glucose and ketone body levels were assessed to determine metabolic status, followed by a battery of behavioral tests to assess general activity levels, cognitive function, and anxiety‐related behaviors.ResultKD resulted in nutritional ketosis, attenuated body weight and adiposity, lowered fasting and fed blood glucose levels, improved glucose tolerance, increased activity levels (open field, Y‐maze), and enhanced spatial learning and memory (Barnes maze). Additionally, mice fed with KD exhibited a positive trend toward improved spatial working memory (Y‐maze for spontaneous alternation).ConclusionTaken together, these findings provide compelling evidence that KD positively impacts cognitive performance and metabolic function, suggesting it may be a viable therapeutic option for CAA. Future research should explore the therapeutic potential of KD in females, as well as the diets' long‐term efficacy.
Variant‐to‐function mapping of late‐onset Alzheimer’s disease GWAS loci in human microglial models implicates RTFDC1 as an effector gene at the CASS4 locus
Authors: Burton Elizabeth A , Argenziano Mariana , Cook Kieona , Ridler Molly , Su Chun , Manduchi Elisabetta , Hodge Kenyaita M , Wang Li‐San , Schellenberg Gerard D. , Pippin James A. , Wells Andrew D. , Anderson Stewart A. , Brown Christopher D. , Grant Struan F.A. , Chesi Alessandra 
Published: January 2025

AbstractBackgroundTo date, Alzheimer’s disease (AD) research has principally focused on neurons. In contrast, recent studies suggest that genetic mechanisms drive microglia towards prolonged inflammation in AD brains, exacerbating neurodegeneration. Indeed, many of the 70 disease‐associated loci uncovered with genome‐wide association studies (GWAS) reside near genes related to microglial function, such as TREM2. However, GWAS cannot directly identify causal variants or effector genes, as GWAS only reports the sentinel variant at a given locus, which tags all variants in high linkage disequilibrium. We used a combination of ATAC‐seq and high‐resolution promoter‐focused Capture‐C in two human microglial cell models to map interactions between GWAS‐implicated variants and their putative effector genes. We then validated an observed interaction between SNP rs6024870 at the ‘CASS4’ AD locus and the promoter of RTFDC1, a DNA damage response gene, using CRISPR‐Cas9.MethodWe employed Capture‐C to characterize the genome‐wide interactions of all promoters in the HMC3 microglial cell line and iPSC‐derived microglia. We confirmed enhancer activity of the region harboring rs6024870 using dual‐luciferase assays. To validate the regulatory interaction with the Capture‐C implicated effector gene RTFDC1, we used lentiviral CRISPR‐Cas9 to delete an ∼400bp region containing the SNP in HMC3 cells. We confirmed changes in RNA and protein expression using RNA‐seq and immunoblotting. Furthermore, we assessed DNA damage repair deficiencies in enhancer knockout cells using an immunofluorescent assay for the histone mark GH2AX, and confirmed the role of RTFDC1 in the DNA damage phenotype using siRNA knockdown and lentiviral overexpression of RTFDC1, respectively.ResultProxy SNP, rs6024870 (r2 = 0.93 to sentinel rs6014724), at the ‘CASS4’ locus, coincided with open chromatin and contacted the promoter of RTFDC1. Deletion of the putative enhancer region harboring rs6024870 by CRISPR‐Cas9 in HMC3 reduced the expression of both RTFDC1 mRNA and protein. Knockout cells had reduced ability to clear DNA double‐strand breaks (DSBs), and siRNA knockdown and lentiviral overexpression of RTFDC1 confirmed this phenotype was due to reduction of RTFDC1.ConclusionWe implicate rs6024870 and RTFDC1 as a SNP‐effector gene pair at the AD ‘CASS4’ GWAS locus, and the gene product is directly involved in driving a reduction in DNA DSB clearance.
Heart rate and electrodermal activity during key driving events in older adult drivers with and without elevated amyloid burden
Authors: Kumar Anu M , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Bross Jordan R , Flynn Emma , Koeppe Robert A. , Giordani Bruno 
Published: January 2025

AbstractBackgroundEarly symptoms of Alzheimer’s disease (AD) may include subtle performance changes in complex tasks, such as driving, which could be potential markers for identifying those at risk of cognitive decline. In this study, categorical driving behaviors and events as well as related physiological changes were compared in older adults with and without elevated brain amyloid.MethodVideo and physiological data collected from 21 amyloid positive and 21 amyloid negative participants over the age of 65 (range 65‐85), who participated in the University of Michigan’s Driving and Physiological Responses study were analyzed. Amyloid positivity was determined based on the PET centiloid scale. All drivers completed the same fixed course route. Road‐ and driver‐view videos of each participant were annotated to mark 69 key road events and driving behaviors (e.g., if the participant made a rolling or full stop). Heart rate (HR) and electrodermal activity (EDA) data collected through an Empatica E4 watch were obtained for each road event and categorized as “high” or “low”. Physiological responses were considered “high” if they exceeded the driver’s average physiological response during the fixed course drive and “low” if they did not. Chi‐square analyses were used with a p‐value of ≤ 0.05.ResultOlder adults with high amyloid burden exhibited a higher frequency of rolling through stop signs compared to their amyloid negative peers and exhibited “high” HR responses during this event. Amyloid positive drivers were also more likely to exhibit a “high” HR at intersections without traffic signs and when encountering medium/high traffic loads. No significant patterns in EDA were found.ConclusionAmyloid positive older drivers exhibited relatively elevated HR responses while driving in more complex situations (at stop signs or heavier traffic). This pattern of driving behavior and accompanying physiological responses that account for participants’ individual variability may indicate an early sign of cognitive change in older individuals with high amyloid burden. These attributes can be used as effective features to build a Machine Learning‐based AD diagnosis tool to detect early‐stage AD in older drivers.
Repetitive injury causes Alzheimer’s disease‐like phenotypes via reactivation of HSV‐1 in a 3D human brain tissue model
Authors: Cairns Dana M , Smiley Brooke M , Smiley Jordan A , Khorsandian Yasaman A , Kelly Marilyn A , Itzhaki Ruth F , Kaplan David L 
Published: January 2025

AbstractBackgroundMillions of people suffer from traumatic brain injury (TBI) annually and many subsequently develop AD‐like characteristics, but the processes occurring in the brain and the reasons for the acquisition of AD‐like dementia are unknown. TBI is the leading cause of mortality in young adults and causes a huge socioeconomic burden. Improving outcomes in these patients would be a significant public health benefit. Evidence indicates that herpes simplex virus type 1 (HSV‐1) in brain of APOE‐e4 carriers confers a strong risk of AD. In a 3D human brain tissue model quiescently infected with HSV‐1, subsequent exposure to other pathogens induces reactivation of the virus via induction of neuroinflammation. We surmised that as TBI also causes neuroinflammation, brain injury might similarly reactivate quiescent HSV‐1.MethodsUsing a mechanical device to initiate closed head injury (CHI), we were able to successfully mimic concussion in 3D tissue engineered constructs consisting of human induced neural stem cells (hiNSCs). We examined the effects of one or more controlled blows to our 3D human brain model in the absence or presence of quiescent HSV‐1 infection, then assessed for downstream AD‐like readouts.ResultsAfter controlled blows, quiescently‐infected 3D brain tissues showed HSV‐1 reactivation, Abeta and P‐tau production, and gliosis; a phenotype that intensified upon increased repetition of injury. We identified a role for mechanical injury in reactivating HSV‐1 and thus producing AD‐like phenotypes, suggesting that concussion can potentially trigger HSV‐1 to initiate AD pathogenesis.ConclusionsWe suggest that after brain injury from repeated mechanical blows in life, the resulting HSV‐1 reactivation in the brain leads to the development of AD/dementia, i.e., that HSV‐1 is a major cause of AD. We hope to discover ways of alleviating the effects of TBI‐induced HSV‐1 reactivation that ultimately lead to AD, and whether other types of brain damage cause similar effects.