bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genes that escape X chromosome inactivation are associated with Alzheimer’s disease endophenotypes: findings from ROSMAP
Authors: Seto Mabel , Clifton Michelle , Coughlan Gillian T , Boyle Rory , Birkenbihl Colin , Wang Ting‐Chen , De Jager Philip L. , Schneider Julie A. , Sperling Reisa A , Wang Yanling , Bennett David A. , Hohman Timothy J. , Yang Hyun‐Sik , Dumitrescu Logan C. , Buckley Rachel F 
Published: January 2025

AbstractBackgroundWomen are disproportionately affected by Alzheimer’s disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI‐escaping genes provide a promising avenue of discovery for biological pathways driving sex‐specific AD risk. Our objective was to examine XCI‐escaping genes in association with β‐amyloid (Aβ) and tau tangle density, and cognitive decline.MethodsUsing bulk RNAseq from dorsolateral prefrontal cortex tissue, Aβ plaque and tau tangle pathology, and antemortem longitudinal cognition data from ROSMAP, we investigated whether XCI‐escaping genes explain significant variance in AD endophenotypes. Propensity scoring based on age‐at‐death, postmortem interval, race, latency‐to‐death, education, and APOEε4 status resulted in a matched sample (N = 648, age‐at‐deathmean(SD) = 87.5(6.5)). Linear regression and mixed‐effects models assessed the association between 216 reported XCI‐escaping genes and Aβ and tau at autopsy, and a longitudinal global cognitive composite. Analyses were sex‐stratified and FDR‐corrected. Differential expression analyses assessed sex‐biased mean gene expression.Results22 XCI‐escaping genes were associated with Aβ (20 female‐specific, 2 male‐specific), 49 genes with tau (43 female‐specific, 6 male‐specific), and 48 genes with cognitive decline (46 female‐specific, 2 male‐specific). In women, 40%(8/20) were negatively associated with Aβ, 56%(24/43) negatively associated with tauopathy, and 43%(20/46) were negatively associated with cognitive decline. Of note, higher GRIPAP1 expression was associated with lower Aβ (β = ‐0.18, pFDR = 0.02) and tau (β = ‐0.21, pFDR = 0.001), and slower cognitive decline (β = 0.02, pFDR = 0.04) in women. By contrast, ATP11C expression was associated with higher Aβ (β = 0.19, pFDR = 0.03) and tau (β = 0.15, pFDR = 0.03), and faster cognitive decline (β = ‐0.02, pFDR = 0.03) in women. Unexpectedly, of 216 XCI‐escaping genes tested, only 4% were expressed more highly in females than males.ConclusionGRIPAP1 and ATP11C are implicated in endosomal recycling and inflammation, respectively, supporting two pathways associated with AD. Both GRIPAP1 and ATP11C exhibited sex‐parity in gene expression suggesting that single‐cell RNAseq will be necessary to further characterize XCI‐escapism in relation to AD risk. Altogether, this study presents evidence that studying the X chromosome is integral to understanding female resistance, resilience, and vulnerability to AD pathology.
Sleep and Delirium: Understanding Links, Mechanisms, and Associations with Neurodegenerative Conditions
Authors: Krystal Andrew 
Published: January 2025

AbstractThose with neurodegenerative conditions have an increased risk of developing delirium and there is some evidence that delirium may be a risk factor for neurodegenerative disorders. Similar to the interactions between sleep and neurodegenerative conditions, there is increasing evidence for bi‐directional relationships between delirium and sleep disorders and disturbances. This presentation will provide an overview of the literature on those relationships, including discussion of the well‐characterized changes in sleep that occur in individuals experiencing delirium. Evidence that sleep disorders and disturbed sleep increase the risks of delirium and that treatments addressing sleep disorders decrease those risks will also be reviewed. Studies have demonstrated that both obstructive sleep apnea and sleep disturbance significantly increase the risk of post‐operative delirium, and post‐operative delirium is associated with an increased risk of cognitive decline and possibly dementia There is a growing set of studies assessing the degree to which pharmacologic therapies that address disturbed sleep, including dual orexin receptor antagonists, melatonin, and melatonin receptor agonists, mitigate those risks. Studies of the effects of behavioral interventions aimed at diminishing sleep disturbance in the hospital will also be discussed. In addition, studies assessing whether treating obstructive sleep apnea with continuous positive airway pressure therapy decreases risks for the emergence of delirium will be reviewed. Implications of these studies for understanding the mechanisms by which sleep and delirium are linked and which might explain why neurodegenerative conditions increase the risks for delirium will also be considered. Lastly, the need for future efforts will be presented including rigorous mechanistic studies, larger well‐controlled trials of treatments and development of clinical care paths.
An AluYb8 mobile element characterises the risk haplotype of the TMEM106B locus associated with neurodegeneration
Authors: Salazar Alex N , Tesi Niccoló , Pijnenburg Yolande A.L. , van der Lee Sven J , Knoop Lydian , Wijesekera Sanduni , Krizova Jana , Hiltunen Mikko , Damme Markus , Petrucelli Leonard , Reinders Marcel JT , Hulsman Marc , Holstege Henne 
Published: January 2025

AbstractBackgroundThe TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome‐wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD‐TDP). However, the causal variant that drives the association has thus far remained elusive.MethodsWe generated long‐read whole‐genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.ResultsWe identified an insertion of an AluYb8 retrotransposon in the 3’ UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk‐SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a ‘copy‐paste’ mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3’ UTR of TMEM106B orthologs in non‐primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry‐receptor for specific viruses in lung‐tissue, such that SINE‐mediated downregulation of TMEM106B may limit viral infection‐load across species.ConclusionsWe speculate that AluYb8‐mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP‐43, in its role in post‐translational RNA‐processing. This leads us to further speculate that age‐related demethylation and age‐related dysregulation of TDP‐43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.
Association of mitochondrial DNA variants with Alzheimer’s disease phenotypes in 500K participants with whole genome sequencing from the UK Biobank
Authors: Tabar Mohsen Sharifi , Cui Biqi , Liu Chunyu , Zare Habil , Satizabal Claudia L , Seshadri Sudha , Jian Xueqiu 
Published: January 2025

AbstractBackgroundMitochondria are organelles where energy production takes place via oxidative phosphorylation, thus mitochondrial function influences the organs with large energy consumption, such as the brain. Mitochondria contain their own circular genome (mtDNA), which encodes essential proteins/RNAs involved in oxidative phosphorylation. The maternal inheritance of mtDNA, combined with a higher risk of Alzheimer’s disease (AD) observed in females, suggest mtDNA may have a role in AD. Yet, our knowledge of the impact of mtDNA on AD remains limited, and large‐scale association studies of mtDNA variation and AD are lacking.MethodUsing whole genome sequencing (WGS) data from 500K UK Biobank participants, we called mtDNA variants with MitoHPC. Three phenotypes were derived from ICD‐10 codes: AD, all dementia, and AD‐by‐proxy. Controls were free from dementia and stroke. Participants <60 years of age or non‐European white were excluded from the preliminary analysis. We assessed the association between each mtDNA variant (minor allele count ≥30) and the three phenotypes, respectively, adjusting for age, sex, assessment center, genetic principal components, and genetic relationship matrix. Additional analyses were performed with adjustment of APOE ε2/ε4 count. Significance was set at 5 × 10−5, or the equivalent of correcting for ∼1000 independent mtDNA haplotypes in the dataset.ResultAfter exclusions, up to 283,868 samples were left in our analyses, including 3742, 8459, and 53,417 with AD, all dementia, and AD‐by‐proxy, respectively. We observed suggestive associations (p<10−3) between mtDNA variants and AD phenotypes (Table), including a synonymous variant in MT‐ND5 with both AD and all dementia. Additionally, another synonymous variant in MT‐CO2 was suggestively associated with AD only. The analysis of AD‐by‐proxy identified multiple variants of interest upstream of MT‐ND1. All three genes encode essential enzymes in the electron transport chain and were previously found to be overly expressed in blood in early AD.ConclusionOur preliminary analysis of the 500K WGS data from the UK Biobank suggested associations between multiple mtDNA variants and AD phenotypes. Robust aggregation tests suited for rare variants are underway to assess the vast majority of the mtDNA variants (rarer) identified by WGS. Inclusion of diverse samples is warranted to reveal ancestry‐specific effect of mtDNA variation on AD.
Seizure‐activated neurons facilitate tau spread in 5XFAD mice
Authors: Barbour Aaron J , Chavez Abigail , Hoag Keegan , Li Xiaofan , Hassman Chloe , Lee Virginia M.‐Y. , Talos Delia M , Jensen Frances E 
Published: January 2025

AbstractBackgroundSeizures are highly comorbid with Alzheimer’s disease (AD). We and others have demonstrated worsened pathological and cognitive outcomes in AD patients with seizure history and after seizure induction in AD mouse models. Central to AD progression is the spread of tau along neuronal connections, which can be modelled by intracerebral injection of human AD brain derived tau lysate (AD‐tau), but whether seizures impact the spread of tau is unknown. We hypothesized that seizures would worsen tau spread and that neurons activated during seizures would have increased susceptibility to develop and possibly transmit tau pathology.MethodsTo investigate seizure‐tau interactions, we crossed the 5XFAD mouse model with targeted recombination in active populations mice (TRAP; 5X‐/WT‐TRAP) to permanently label seizure‐activated neurons. We injected AD‐tau unilaterally into the hippocampus and overlying cortex (1 µg/site) at three months of age in 5X‐TRAP and WT‐TRAP littermates. Seizures were then induced with pentylenetetrazol (PTZ) kindling 2‐3 weeks following surgery and seizure‐activated neurons were induced to express tdTomato on the final day of kindling via 4‐hydroxytamoxifen administration. Three months following AD‐tau seeding, 5X‐/WT‐TRAP brains were serially sectioned and underwent immunofluorescent slide scanning. Scanned brain images were then registered to the Allen Brain Atlas and mapped for seizure‐activated neurons (tdTomato+) and tau pathology (phospho‐tau Ser202/Ser205; AT8).ResultsWe found that 5X‐TRAP mice had increased tau pathology compared to WT‐TRAP in hippocampal subregions ipsilateral to AD‐tau injection, including the dentate gyrus (p<0.05, n = 5‐10/group) and subiculum (p<0.01, n = 5‐9/group), regardless of seizure kindling, without changes in the contralateral hippocampus. Seizure induction resulted in increased tau spread in remote interconnected brain regions, including the ipsilateral and contralateral thalamo‐cortical regions (p<0.05, n = 5‐9/group). In addition, we found that, compared to neurons from a saline‐treated 5XFAD mouse, thalamic seizure‐activated (tdTomato+) neurons showed significantly increased somatic AT8 levels (p<0.05, n = 8‐11), while surrounding (tdTomato‐) neurons from 5XFAD mice did not, suggesting that these thalamic, seizure‐activated neurons preferentially facilitate tau spread.ConclusionTogether, our data demonstrate that seizures increase tau spread in mouse models and identify seizures and seizure‐activated neurons as therapeutic targets to slow pathological AD progression.
The modified Rowland Universal Dementia Assessment Scale for dementia screening in Peruvian population
Authors: Custodio Nilton , Montesinos Rosa , Malaga Marco , Custodio Belen , Chambergo‐Michilot Diego , Bustamante‐Paytan Diego , Yauri Zadith , Aguero Katherine , Verastegui Graciet , Lanata Serggio , Butler Christopher , Tosto Giuseppe 
Published: January 2025

AbstractBackgroundTranscultural adaptations of brief cognitive screening tools (BCTs) involve the development of alternate versions that are psychometrically equivalent to the original, while being linguistically and culturally adapted to a new sociodemographic context. The RUDAS (Rowland Universal Dementia Assessment Scale) is less affected by culture, language, and education compared with other BCTs. However, several studies have reported an effect of education on RUDAS scores. In Peru, performance on visuospatial construction and judgement items of the RUDAS may be particularly low amongst rural communities. The main aim of this study was to evaluate the performance of a culturally‐refined version of the Peruvian version of RUDAS (RUDAS‐PE), the RUDAS‐PEm. We tested how well the RUDAS‐PEm distinguished between controls and patients with Alzheimer’s disease (AD), behavioral variant frontotemporal dementia (bvFTD), and other types of dementia, compared to the RUDAS‐PE.MethodTo create the RUDAS‐PEm, we modified two domains of RUDAS‐PE, visuo‐spatial construction and judgement, to psychometrically‐congruent alternatives that are more appropriate for the Peruvian context. We changed the ‘cube drawing’ task (visuospatial construction) to drawing a circle, rhombus, and rectangle. The ‘crossing the street in transit’ task (judgement) was changed to one asking patients to tell the difference between sugar and vinegar and to explain how to locate a new friend in a new city.ResultsWe included 110 controls and 87 patients with dementia: 54 with AD, 20 with bvFTD, and 13 with other dementias. Mean age was 70 (SD 7.8) and mean education was 14.2 years (SD 4.1). For visuospatial construction in RUDAS‐PE, there were significant differences between the scores of controls and AD patients (<0.001), bvFTD patients (0.02), and other dementias (p<0.001) (figure 1). For RUDAS‐PEm, no significant differences were found between scores of controls and bvFTD patients. For the judgment item both versions had good discrimination, but RUDAS‐PEm showed better performance (table 1). The times to complete both versions and the AUC for diagnosis of AD versus controls, bvFTD versus controls, and all dementias versus controls, were similar in both versions.ConclusionThe RUDAS‐PEm including modification of the judgment item shows modest improvement in detecting dementia.
Alzheimer’s disease multiomic signatures mediated by Cholesterol Ester Transfer Protein
Authors: Abel Tamar R , Pandey Ravi S , Spruce Catrina , Poliakova Tetiana , Wellington Cheryl L , Carter Gregory W 
Published: January 2025

AbstractBackgroundAltered lipid profiles and lipid processing genes are associated with Alzheimer’s disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD. Additionally, previous studies in transgenic humanized CETP (hCETP) mice have demonstrated that CETP addition in mice increases expression of AD risk genes and markers of AD pathogenicity. Together, this suggests that CETP may modify AD risk in an APOE4‐dependent manner. This project aims to determine molecular pathways and signatures in AD mediated by CETP with an emphasis on molecular pathways shared with APOE as a potential disease‐altering mechanism.MethodsTo identify pathways shared by CETP and APOE we created molecular networks using publicly available online tools including the AD Atlas and STRING (v12.0). The Heart and Diabetes Institute Metabolomics Laboratory Portal was leveraged to perform Genome Wide Association Study (GWAS) analysis to establish changes in lipid species abundance shared by CETP and APOE genetic variants. Transcriptional signatures in several mouse models were compared to human AD gene modules to determine pathological relevance of hCETP and APOE4 mouse models.ResultsMolecular networks implicated several genes as being co‐expressed suggesting they may co‐function with CETP and APOE. These co‐expression edges included C4A/B compliment genes, PSMB8, APOJ/CLU, and APP. GWAS analysis resulted in several notable findings including that CETP variants have a strong effect on the relative abundance of phosphatidylcholine (PC) lipid species. Additionally, while APOE4 is positively associated with total PC, the common loss‐of‐function variant CETP I405V (rs5882) is associated with reduced PC levels. Transcriptional changes in lipid‐related transgenic and MODEL‐AD knock‐in mouse models exhibited significant associations with immune processes.ConclusionsThese findings indicate that both CETP and APOE influence total PC and are associated with molecular pathways of immune activation and amyloid biology. Overall this evidence suggests that CETP and APOE act on shared pathways, likely mediated by lipid metabolism and peripheral immunity, that contribute to AD susceptibility.
The Quick Dementia Rating System and the Clinical Dementia Rating Scale: Investigation of agreement and related features in a predominantly unimpaired sample
Authors: Huang Qi , Bolt Daniel M. , Jonaitis Erin M. , Hermann Bruce P , Studer Rachel L , Ryther Brenda , Sparks Lia J. , Galvin James E , Johnson Sterling C. , Langhough Rebecca E. 
Published: January 2025

AbstractBackgroundThe Clinical Dementia Rating Scale (CDR) is a gold standard metric for staging the nature and severity of global cognitive and functional impairment in Alzheimer’s disease (AD) and other dementias. Prior evidence from older and/or smaller samples suggests that The Quick Dementia Rating System (QDRS) informant questionnaire provides results comparable to the CDR and can be completed in just 3‐5 minutes, sans a trained clinician or rater. This study aimed to: 1) investigate concordance between the QDRS‐derived global CDR (“QDRS‐global”; Galvin, 2015) and CDR‐global scores; 2) examine item‐level QDRS/CDR agreement; and (3) evaluate QDRS‐global/CDR‐global concordant/discordant groups against concurrent Preclinical Alzheimer’s Cognitive Composite (PACC3) performance.MethodThe study included 351 QDRS/CDR pairs (n = 297 participants) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Analyses include descriptive indices of QDRS/CDR agreement (e.g., QDRS‐global false negative [FN], false positive [FP] rates relative to CDR‐global scores (each collapsed to 0 = unimpaired;.5 = impaired due to few values>.5), Lasso logistic regression identifying QDRS items associated with discordance, tetrachoric correlations evaluating psychometric functioning of CDR and QDRS items, and linear mixed models examining associations between QDRS/CDR concordant/discordant groups and PACC3 performance.ResultThe QDRS‐global/CDR‐global scores concordance rate was 70.66% (see also Table 1). Relative to CDR‐global, the QDRS‐global FP and FN rates were 39.2% and 11.3%, respectively. Item‐level results were consistent with this pattern for all item pairs, except for FuncHome/HomeHob showing a greater tendency for QDRS FNs. Logistic regression and psychometric analyses highlighted the QDRS Memory item as primarily responsible for FPs and FNs (Figure 1). After adjusting for covariates, QDRS‐concurrent PACC3 scores differed significantly for two pairs of QDRS‐global/CDR‐global concordance/discordance groups — True Negative (TN) vs. True Positive (TP), FP vs. TP (Table 2; Tukey‐adjusted pairwise comparisons). The latter suggests that QDRS‐global classification of impairment is more likely to be a FP‐misclassification for participants with high PACC3 scores than for those with low PACC3 scores.ConclusionIn this late‐middle‐aged, predominantly unimpaired sample, the QDRS appears well‐suited for screening for impairment. Future analyses will examine whether more nuanced scoring of the QDRS Memory item may reduce FP and FN rates and will investigate relations to biomarkers for AD and other dementias.