bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower serum vitamin D aggravates hippocampal neurodegeneration related with amyloid pathology
Authors: Park Junha , Byun Min Soo , Yi Dahyun , Ahn Hyejin , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Sohn Chul‐Ho , Lee Yun‐Sang , Kang Kyoung Mi , Lee Dong Young 
Published: December 2023

AbstractBackgroundPrevious studies reported the associations between vitamin D deficiency and increased risk of Alzheimer’s disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults.MethodNondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses.ResultA total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure).ConclusionThe present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration.
Red flags and symptom overlap in anti‐IgLON5 disease and dementia with Lewy bodies – a systematic review
Authors: McWilliam Oskar , Gramkow Mathias H. , Blaabjerg Morten , Clemmensen Frederikke Kragh , Hasselbalch Steen G. , Frederiksen Kristian Steen 
Published: December 2023

AbstractBackgroundAnti‐IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is a type of autoimmune encephalitis (AE) but unlike other AEs anti‐IgLON5 disease has an insidious onset and prominent tau pathology. Anti‐IgLON5 disease mimics neurodegenerative disorders and multiple symptoms overlap with the second most common cause of neurodegenerative dementia, Dementia with Lewy bodies (DLB). The purpose of this review was to assess the overlap in features between anti‐IgLON5 disease and DLB and to identify potential red flags for anti‐IgLON5 disease in patients undergoing diagnostic evaluation for DLB.MethodWe conducted a systematic review of reports on features of anti‐IgLON5 disease from full‐text articles in MEDLINE, Web of Science, and Embase. The reviewed data was compared to consensus criteria for DLB.ResultWe included 57 studies with a total of 125 cases of anti‐IgLON5 disease. The median age was 61 years at diagnosis, with a median symptom duration of 3.5 years. Ten % (13/113 cases) presented with cognitive dysfunction. REM‐sleep disorder was diagnosed in 43% (17/39 cases), and movement disorders were present in 73% (80/110 cases) of which parkinsonism was identified in 21% (18/85 cases). In 47% (25/59 cases), psychiatric disturbances were reported, and hallucinations were observed in 37% (11/30 cases). Dysautonomia was reported in 56% (42/75 cases). Regarding red flags for anti‐IgLON5 disease, bulbar symptoms were observed in 75% (82/109 cases) and respiratory insufficiency was in 60% (32/66 cases). Brain MRI was normal in 56% (40/72 cases) and routine cerebrospinal fluid examination was normal in 63% (36/57 cases). Anti‐IgLON5 antibodies were positive in serum in all cases, where serum was tested and positive in cerebrospinal fluid in 96% (71/75 cases).ConclusionWe found a significant overlap between symptoms in anti‐IgLON5 disease and DLB including cognitive dysfunction, REM‐sleep disorders, parkinsonism, and an insidious onset over several years. We propose that anti‐IgLON5 disease should be considered in atypical DLB cases with bulbar or respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti‐IgLON5 disease.
Dementias Platform UK: Bringing genetics into life
Authors: Leonenko Ganna , Bauermeister Sarah , Stevenson‐Hoare Joshua O , Baker Emily A , Gallacher John , Escott‐Price Valentina 
Published: December 2023

AbstractBackgroundDPUK is a data repository bringing together a wide range of population and clinical cohorts from the UK, Europe and South Korea. It enables data discovery, variable selection, and data access for multi‐modal, multi‐cohort analysis in a shared and secure environment. Neurodegenerative dementias are group of diseases with highly heterogeneous pathology and with an overlapping genetic component that is poorly understood. Combing genetic data from different studies is important due to the increase in power this provides, but this presents an additional challenge due to differences in genotyping arrays and lack of overlapping variants.MethodWe have curated and harmonized genome‐wide data from 6 studies (Brains for Dementia Research, EPIC Norfolk, Generation Scotland, Airwave‐chip 1, Airwave‐chip 2, MRC National Survey of Health Development (NSHD)) within the DPUK platform. We created a pipeline that performs rigorous quality‐control (QC) analysis and imputes genetic variance with the 1000 Genome reference panel using the minimac algorithm. Further, standard pruning and thresholding Polygenic Risk Score (PRS) have been generated with 5 summary statistics related to neurodegenerative diseases (clinical AD, clinical/proxy AD, FTD, ALS, PD) for all 6 studies separately and for the combined dataset.ResultResearch‐ready imputed genetic data that have undergone QC and the PRS, based upon the latest neurodegenerative GWAS, are available for the 6 cohorts separately, and for the combined dataset of 60,670 individuals.ConclusionPreparing multiple datasets to a common standard for research‐readiness increases scientific opportunity and allows the wider research community to access and process data at scale and pace.
Widespread transposable element dysregulation in human brains with Alzheimer’s disease
Authors: Feng Yayan , Hou Yuan , Zhou Yadi , Leverenz James B , Pieper Andrew A. , Cheng Feixiong 
Published: December 2023

AbstractBackgroundTransposable elements (TEs), known as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. However, transposable element (TE) dysregulation of quantitative trait loci (QTL) has not been well‐characterized in human disease, such as Alzheimer’s disease (AD).MethodIn this study, we present the first catalog of transposable element quantitative trait loci (teQTLs) in human brains. By leveraging large‐scale RNA‐sequencing (RNA‐seq), whole‐genome sequencing (WGS), and various QTL data (xQTL) from three brain biobanks with Alzheimer’s disease (AD), we comprehensively characterize TE dysregulation across diverse AD pathobiology, including Tau, amyloid beta, APOE genotypes, and sex differences. We further integrate different types of QTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls to identify AD likely causal genes regulated by brain teQTLs through colocalization analysis. Regulatory roles of brain teQTLs are dissected via long‐range cell type‐specific enhancer‐promoter chromatin interaction maps.ResultJoint‐analysis of WGS and RNA‐seq data identified 77,335 genome‐wide significant TE expression QTLs (teQTLs) in human AD brains. Colocalization analysis of teQTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls identified key AD likely causal genes regulated by brain teQTLs. This identified new AD risk genes, including complement C1q tumor necrosis factor‐related protein 4 (C1QTNF4) and farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). A TE from Plat_L3 subfamily (chr11: 47605296‐47605575) suppressed expression of C1QTNF4 (its nearest gene) via long‐range enhancer‐promoter chromatin interaction in neurons. We identified that a TE from AluSz6 subfamily (chr8: 11834847‐11835127) increased expression of FDFT1 (its nearest gene) via microglia‐specific long‐range chromatin looping. Expression perturbation of FDFT1 and C1QTNF4 were significantly correlated with Braak staging score of AD patients. We further identified that individuals with AD risk allele APOE4 displayed elevated expression of AluSz6 and FDFT1 in patient induced pluripotent stem cells (iPSC)‐derived microglia and superior frontal gyrus (SFG) microglia compared to APOE3 individuals.ConclusionThese findings demonstrate widespread TE dysregulation in human brains and teQTLs offer a useful QTL analytic approach to identify AD risk genes and other complex diseases if broadly applied.
Isoform characterisation & splicing signatures of AD‐risk genes using long‐read sequencing
Authors: Leung Szi Kay , Castanho Isabel , Jeffries Aaron , Moore Karen , Dempster Emma , Brown Jonathan T , Bamford Rosemary , Hannon Eilis , Mill Jonathan 
Published: December 2023

AbstractBackgroundAn increasing number of studies implicate a role for alternative splicing in development and neuropathology of Alzheimer’s disease (AD). However, it has been historically challenging to characterise splicing events, due to the inherent limitations of traditional RNA‐sequencing (RNA‐Seq) to capture full‐length transcripts critical for transcriptome assembly. In this study, we use two complementary targeted long‐read sequencing approaches, Pacific Biosciences (PacBio) isoform sequencing (Iso‐Seq) and Oxford Nanopore Technologies (ONT) nanopore cDNA sequencing, to profile the cortex of a mouse model of tau pathology (rTg4510) with ultra‐deep sequencing of a panel of 20 genes robustly implicated in AD.MethodTargeted PacBio Iso‐Seq and targeted ONT profiling were performed on RNA isolated from 24 female rTg4510 transgenic and wild‐type mice, aged 2, 4, 6 and 8 months. Following successful enrichment for target genes using custom‐designed probes (IDT), library preparation were performed for subsequent sequencing on Sequel and MinION. The panel of genes selected for enrichment included genes (i.e. App, Mapt, Snca) and dementia risk genes identified from GWAS analyses. Raw sequence data was processed using a customised bioinformatics, and full‐length reads were merged and annotated with our developed custom scripts (FICLE).ResultWe identify thousands of novel transcripts across the panel of 20 AD‐ and dementia‐associated genes. We reveal unprecedented diversity of alternatively‐spliced isoforms with widespread usage of alternative novel 5’ and 3’ splice sites. We further robust transcriptional and splicing differences in these AD‐risk genes associated with the development of tau pathology. Among these changes, we observed global up‐regulation of Trem2‐associated isoforms and isoform switches in Bin1, further supporting a role for the dysregulation of the immune response in the development of AD pathology.ConclusionThis represents the first study to comprehensively assess variable AS associated with the development of tau pathology using both PacBio Iso‐Seq and ONT nanopore sequencing. Our analyses confirm the importance of alternative RNA splicing in AD and identify evidence of differential transcript usage, even in the absence of gene‐level expression alterations. Further work will be undertaken to validate and functionally characterise these novel isoforms, and to extend these analyses to human post‐mortem AD brain samples.
DAT1 and BDNF polymorphisms interact to predict cross‐sectional and longitudinal amyloid and tau pathology in cognitively normal older adults
Authors: Ciampa Claire J , Murphy Alice , La Joie Renaud , Jagust William J. , Landau Susan M. , Berry Anne S. 
Published: December 2023

AbstractBackgroundDysfunctional dopamine signaling and disruptions in neurotrophic support are potential exacerbators of Alzheimer’s disease (AD) pathophysiology. A single nucleotide polymorphism (SNP) in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) is associated with greater ventricular expansion and lower scores on the Mini Mental State Exam (MMSE; Roussotte et al., 2015). A polymorphism in the brain derived neurotrophic factor gene (Val66Met in BDNF) is related to greater hippocampal atrophy and more severe episodic memory decline for amyloid positive Met carriers (Lim et al., 2013). However, it is unclear whether and how these polymorphisms directly relate to AD pathology.MethodWe tested a moderated mediation model (Fig. 1) involving both BDNF and DAT1 polymorphisms in a sample of cognitively normal older adults (n = 321) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This mediation involved DAT1 (independent variable), b‐amyloid (Ab; mediator), and tau pathology (dependent variable) with BDNF as a moderator. Ab and tau were measured both cross‐sectionally and longitudinally with positron emission tomography (PET) tracers [18F]Florbetapir/[18F]Florbetaben and [18F]Flortaucipir, respectively.ResultA significant moderated mediation demonstrated that DAT1 and BDNF interacted to predict cross‐sectional Ab‐PET (p = .02) and tau‐PET (p = .04), such that carriers of both DAT1 C and BDNF Met alleles demonstrated greater pathology (Fig. 2), consistent with previous research associating these variants with AD symptoms. Longitudinal analyses replicated these cross‐sectional results, with DAT1 C and BDNF Met carriers exhibiting greater accumulation of tau pathology (p = .0002) and marginally increased Ab accumulation (p = .07).ConclusionOur analyses revealed novel interaction effects between genetic polymorphisms in the DAT1 and BDNF genes. These results suggest that carrying DAT1 CC and BDNF Met results in higher Ab, which then contributes to higher tau pathology. While our analyses do not demonstrate causality, these findings are consistent with current hypotheses of AD in which Ab drives increases in tau pathology (Karran et al., 2011).
The AD/ADRD Interdisciplinary Research Network on Biologically Active Tau Aggregate Polymorphs from Alzheimer’s Disease and Related Dementias
Authors: Kayed Rakez , Kuret Jeff , Keene C Dirk , Eisenberg David S. 
Published: December 2023

AbstractBackgroundTauopathies, including Alzheimer’s disease (AD), are characterized by intracellular lesions composed of aggregated and post‐translationally modified tau proteins. Methods for preparation and biochemical characterization of stable filaments from various tauopathies are well established. In contrast, methods for preparation of soluble oligomeric tau aggregates have not been standardized to the same degree. Additionally, the structures of oligomers which associate most closely with disease propagation and toxicity, are not fully established. The AD/ADRD Resource Network aims to isolate structurally vetted tau filaments and oligomers from human tauopathy cases and distribute them to the research community. In addition, it seeks to bank and distribute detection reagents and associated protocols. The overall mission of the network is to support impactful tauopathy research.MethodTauopathies, including Alzheimer’s disease (AD), are characterized by intracellular lesions composed of aggregated and post‐translationally modified tau proteins. Methods for preparation and biochemical characterization of stable filaments from various tauopathies are well established. In contrast, methods for preparation of soluble oligomeric tau aggregates have not been standardized to the same degree. Additionally, the structures of oligomers which associate most closely with disease propagation and toxicity, are not fully established. The AD/ADRD Resource Network aims to isolate structurally vetted tau filaments and oligomers from human tauopathy cases and distribute them to the research community. In addition, it seeks to bank and distribute detection reagents and associated protocols. The overall mission of the network is to support impactful tauopathy research.ResultProtocols for simultaneous isolation of oligomeric and filamentous tau aggregates have been developed along with analytical and quantitative methods to estimate sample heterogenicity and stability. Resource Network members are establishing cross‐laboratory analytical benchmarks for experiments to ensure rigor and reproducibility of results.ConclusionThe AD/ADRD Research Network banks rigorously validated preparations of structurally vetted tau aggregates along with directed protocols and reagents. Dissemination of these reagents is expected to maximize rigor and reproducibility of basic research involving tau protein aggregates.
Antemortem visit‐to‐visit blood pressure variability and postmortem cerebrovascular disease lesion burden in older adults without dementia
Authors: Sible Isabel J , Nation Daniel A. 
Published: December 2023

AbstractBackgroundBlood pressure management is an accessible therapeutic target for dementia prevention. Beyond the current focus of managing mean levels, there is a burgeoning interest in understanding the variability in blood pressure levels. Emerging research suggests elevated blood pressure variability is associated with increased risk for Alzheimer’s dementia and cerebrovascular disease, including white matter hyperintensities on MRI (e.g., Fazekas score), but relationships with white matter lesions and overall cerebrovascular pathology at autopsy remain understudied. The aim of the current study was to determine whether antemortem blood pressure variability predicts cerebrovascular pathology in older adults without clinical dementia.Method1866 older adults from the National Alzheimer’s Coordinating Center study underwent repeated approximately annual blood pressure measurement and autopsy and were free of clinical dementia at study baseline. Visit‐to‐visit blood pressure variability was calculated as variability independent of mean using at least 3 (median 5, range 3 ‐ 15) annual blood pressure measurements. White matter rarefaction was scored as none vs mild/moderate vs severe. An index of overall cerebrovascular lesion burden (range 0‐7) was calculated as the sum of severity (0‐2) of atherosclerosis in the Circle of Willis and arteriolosclerosis, and the presence/absence (0‐1) of microinfarcts, infarcts and lacunes, and microbleeds and hemorrhages. Linear and multinomial logistic regression models examined relationships between blood pressure variability, white matter rarefaction severity, and overall cerebrovascular lesion burden, controlling for age, sex, mean blood pressure, antihypertensive use, and Hachinski Ischemic Score, among other variables.ResultElevated blood pressure variability predicted increased severity of white matter rarefaction (OR of mild/moderate [vs none] = 1.21 [1.06, 1.33], p = .004; OR of severe [vs none] = 1.30 [1.07, 1.46], p = .008), and greater overall cerebrovascular lesion burden (ß = .12 [.11, .42]; p < .0001).ConclusionElevated blood pressure variability is related to postmortem cerebrovascular lesion burden, including increased severity of white matter rarefaction, in older adults without clinical dementia, independent of mean blood pressure. Findings are consistent with studies using MRI‐based markers of cerebrovascular disease and may help improve blood pressure as a risk indicator for dementia and cerebrovascular disease.
Infections contribute to proteinopathies in neurodegenerative diseases and in some post‐viral persistent symptoms
Authors: Rheault Sylvie , Duchesne Simon , Belleville Sylvie 
Published: December 2023

AbstractBackgroundThe failure of therapies directed against amyloid‐beta makes us reconsider the theory of the amyloid cascade in Alzheimer’s disease (AD). Infections are suspected to contribute to the disease process. Co‐infection with herpes simplex virus type 1 (HSV‐1) and cytomegalovirus (CMV) results in a higher odds ratio than an individual heterozygous for APOE 4 to develop AD. The objective is to propose a simplified biological model considering the scientific literature to explain the contribution of infections to proteinopathies resulting in neurodegenerative disease for possible integration into a predictive model.MethodWe performed a narrative review of the literature on the cellular mechanisms affected by HSV‐1, CMV and AD.ResultWe propose an hypothetical model supporting that infections can contribute significantly to the different pathophysiological processes of AD via an increase in the failure of misfolding required to obtain a functional conformation of proteins and a decrease in the clearance of proteins with a potentially toxic conformation. Some important changes also involve immunosenescence, as well as compromise of neurogenesis. Immunosenescence allows latent infections, such as HSV‐1 and CMV, to reactivate, spread, and cause cellular changes favorable to AD development.ConclusionThe model explains the cellular changes observed in AD. Given that effective treatments already exist for many of the infections, additional studies are urgently needed to detail the specific contribution of each infection.
Inequities in Distal Health Services Outcomes of ADRD: The Role of Race/Ethnicity
Authors: Tarraf Wassim 
Published: December 2023

AbstractBackgroundDecades of research point to entrenched health and healthcare disparities by race/ethnicity in the US. These disparities are magnified by illness, particularly so in gradually onsetting late diagnosed progressive diseases such Alzheimer’s Disease and Related Dementias (ADRD). ADRDs impose significant burdens on patients, their families, and their caregivers, have substantial health and social implications, and consume large formal and informal financial resources. The US healthcare system is complex, hard to navigate, and a potential contributor to widening disparities.MethodWe (1) review published work on disparities in health services outcomes among individuals with ADRDs in the context of national survey/observational data, (2) discuss micro, meso, and macro risk and resilience factors that can help reduce or close these disparities, and (3) point to gaps (e.g. in data) needing short and intermediate term focus.ResultWe use findings on distal health services outcomes for ADRD from national survey/observational data (e.g. Health and Retirement Study, and the National Health and Aging Trends Study) focusing on race/ethnicity (and confounding factors).ConclusionAddressing the identified gaps can help direct scientific efforts towards interventions and policies that can move us closer to health and healthcare equity in ADRDs.