bluuebunny/crossref_metadata_2025_split huggingface dataset:
943 variants identified synthesizing chromatin conformation capture and quantitative trait loci with results from the Alzheimer’s Disease Variant Portal study
Authors: Cifello Jeffrey , Kuksa Pavel P. , Wang Li‐San , Leung Yuk Yee 
Published: January 2025

AbstractBackgroundRecent genetic studies have implicated >70 genomic loci associated with the risk for Alzheimer’s Disease. However, the underlying functional mechanisms remain unclear. Several functional genomics (FG) methods such as chromosome conformation (CC) capture technologies and expression quantitative trait loci (eQTLs) have been developed to study the genetic targets. In this study, we aimed at using a large collection of brain eQTL and CC datasets to analyze/identify targets for all of the genetic signals in Alzheimer’s Disease Variant Portal (ADVP), a curated and harmonized database of the main genetic findings from > 200 AD GWAS studies.MethodUsing the Harmonization and Integration Pipeline for Functional Genomics (hipFG), >12,000 eQTL and >400 chromatin interaction datasets (>43M interactions) were harmonized, indexed to allow for rapid genomic search. After filtering for non‐cell‐line derived brain tissues and cell types, 78 eQTL and 9 chromatin interaction datasets remained (25 cell types/tissues). Chromatin interactions were analyzed further if one anchor overlapped with a QTL variant, and the other anchor overlapped with the QTL’s target gene’s promoter. These introduced QTL‐target and interaction pairs. Next, we performed linkage‐disequilibrium (LD) pruning and expansion on all genome‐wide significant variants from studies of non‐Hispanic Whites (NHW) in ADVP and evaluated overlaps with chromosome interactions and eQTLs.ResultAcross 1125 curated ADVP variants (p<5e‐8), 90.84% are from NHW, representing 301 independent signals. We LD‐expanded these to 11,964 unique variants. We observed that 10,888 of these variants (91%) overlap with eQTLs, 5156 (43.1%) overlap with chromatin interaction anchors, and 943 (7.9%) overlap with both QTL‐target and CC pairs. Of these 943 variants, only 14.2% are eQTLs for a nearest gene. The 188 eQTL target genes and 271 genes overlapping interaction anchors combined for 359 unique genes, and pathway analyses on this combined set was significantly enriched for amyloid‐beta metabolism and transmembrane transport. These results are in line with previous findings in the field.ConclusionOur analyses showed that using diverse functional annotations enables the discovery of new target genes not found in one assay alone. The ADVP variant regulated genes (supported by both eQTLs and chromatin interactions) implicated known disease mechanisms.
Objective Criteria for Subtle Cognitive Decline in Aging and Preclinical AD: A Systematic Review
Authors: Thomas Kelsey R. , Edmonds Emily C. 
Published: January 2025

AbstractBackgroundThe field of Alzheimer’s disease and related dementias (ADRD) has continued to move toward earlier detection. Within the 2018 NIA‐AA AD Research Framework, clinical stage 2 recognizes that someone can be cognitively unimpaired but still experience “subtle cognitive decline” as measured by subjective report or evidence of objective decline using neuropsychological measures. While significant attention has been given to methods of assessing subjective cognitive decline, there are no systematic examinations of the operational definitions of subtle cognitive decline using objective neuropsychological measures.MethodWe performed a systematic literature search in PubMed/MEDLINE, Web of Science, and PsycInfo databases for articles with dates ranging from the start of the database through 11/1/2023. Search terms are included in Table 1. Only research studies that included participants aged 50+ without MCI/dementia and described a discrete objective subtle cognitive decline category were included.ResultOf 1361 publications that were initially identified, 73 met criteria for inclusion after a full review of the article (Figure 1). Results showed multiple methods for defining subtle cognitive decline. The 6 most common were: 1) subtle cognitive decline based on a specified cut‐off on a single cognitive test; 2) objectively‐defined subtle cognitive decline (Obj‐SCD) using cut‐offs (e.g., ‐1 SD) on multiple individual neuropsychological measures; 3) cut‐off (e.g., 10th percentile) on a cognitive composite score; 4) “Pre‐MCI” criteria defined using a CDR of 0.5 but normal performance on neuropsychological testing; 5) cut‐off based on longitudinal rate of cognitive decline (e.g., over 1 year); and 6) data‐driven/clustering approach to classification. Each method identified a group that had worse AD‐related outcomes relative to cognitively normal participants.ConclusionAcross multiple methods, there is consistent evidence that objective subtle cognitive decline can be detected prior to MCI and is associated with ADRD biomarkers, neuroimaging results, and faster rates of progression to MCI/dementia. Notably, there is a lack of research of these subtle cognitive decline definitions in racially/ethnically diverse older adults, which is a significant weakness in the literature. Results of our review have implications for clinical trial recruitment and for the ethics and potential use of objective subtle cognitive decline criteria in clinical practice in the future.
Role of primary cerebrovascular cilia in the pathogenesis of blood pressure and Alzheimer’s disease manifestations
Authors: Sunderman Clare , Forero Kathleen , Buqaileh Raghad , Aboualaiwi Wissam 
Published: January 2025

AbstractBackgroundPrimary cilia are solitary membrane‐bound organelles emanating from the apical surface of most mammalian cells. They serve as sensory organelles sampling the extracellular environment and reprogramming the transcriptional machinery in response to changes in fluid flow. Ciliopathies, a group of genetic disorders characterized by disrupted cilia structure and/or function, share common phenotypes such as vascular dysfunction and cognitive impairment. Ciliopathies present with a broad range of clinical symptoms, including hypertension (HTN), developmental delays and cognitive and memory deficits, symptoms also observed in Alzheimer’s Disease (AD). This suggests that cilia may house signaling cascades critical for vascular integrity and learning and memory and may also be important contributors to AD and HTN. Therefore, investigation of cilia function in the vascular system may reveal cilia‐modulating mechanisms in neurodevelopmental processes. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.MethodImmunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations. Alzheimer’s Disease model mice (3xTg) were compared to AChM3R knockout mice in multiple behavioral studies, Fear Conditioning and Barnes Maze, to look at memory and spacial learning. Control, AChM3R, and 3xTg knockout mouse cerebral arteries were immunostained for various cilia markers.ResultWe discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Preliminary studies to examine cognitive function indicate altered cognitive function associated with cerebrovascular cilia dysfunction. The two behavioral studies revealed altered memory and fear learning. The 3xTg AD mice cerebral arteries were found to have longer cilia compared to control and AChM3R knockout mice.ConclusionPrimary cilia play an important sensory role for the regulation of blood pressure and cognitive function.
Socioemotional dysfunction relates to financial exploitation vulnerability in Alzheimer’s disease and behavioral variant frontotemporal dementia
Authors: Lee Jayden J , Reeder Jerica E , Phan Tony X , Keener Lindsey C , Wang Siyi J , Darby R. Ryan 
Published: January 2025

AbstractBackgroundFinancial exploitation vulnerability (FEV) denotes the risk for falling victim to financial fraud and older adults reportedly lose an estimated $36 billion annually to scams. Socioemotional and cognitive impairments are potential risk factors for FEV in older adults with dementia. The present study examines whether the socioemotional measures of sensitivity to unfairness and self‐unawareness of socioemotional dysfunction and brain atrophy are associated with increased risk for FEV in Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD).Method25 AD and 39 bvFTD patients played the Ultimatum Game (UG), a social decision‐making task that assesses participants’ sensitivity to unfairness. FEV was measured by administering the Social Vulnerability Scale (SVS), an informant‐based questionnaire, comprising two factors for FEV (gullibility and credulity) and total financial vulnerability (SvsTotal). We evaluated patients’ unawareness of their own socioemotional dysfunction by administering the Interpersonal Reactivity Index to both patients and their informants and computed difference scores for perspective‐taking (patients’ score minus the informants’ score). Finally, we used voxel‐based morphometry to determine regional atrophy associated with FEV measures.ResultInformant ratings for gullibility, credulity, and SvsTotal were significantly higher in bvFTD compared to AD patients (p<0.0001) while controlling for age, gender and disease severity. Greater acceptance of unfair offers in the UG was associated with higher gullibility (r = 0.42, p<0.03) and SvsTotal (r = 0.40, p<0.03) in both groups. bvFTD showed greater deficits in self‐awareness of perspective‐taking capability than AD patients (p<0.02). Unawareness of socioemotional dysfunction was associated with higher gullibility (r = 0.46, p<0.01) and SvsTotal (r = 0.56, p<0.005) in both groups. Increased gullibility in bvFTD was associated with gray‐matter volume loss in the left temporoparietal junction (LTPJ), a classic theory of mind region (p<0.01, FWE‐corrected).ConclusionOur results suggest that FEV is a more severe problem in bvFTD than AD but distinctly related to socioemotional dysfunction in both groups, including impaired self‐awareness and unwillingness to accept unfair offers in simulated social decision‐making tasks. LTPJ atrophy, critical to perspective‐taking, may also increase FEV susceptibility. Both socioemotional dysfunction itself, and a patient’s lack of awareness for their own deficits (i.e., anosognosia) may potentially be an important early risk factor for FEV.
Sex differences in the effects of adolescent stress in an Alzheimer’s disease mouse model
Authors: Groom Emily , Thrasher Christina A , Herzog Ava , Zuloaga Damian G , Zuloaga Kristen L 
Published: January 2025

AbstractBackgroundStress is a common modifiable risk factor for AD, which increases dementia risk 2‐fold. During the stress response, the hypothalamic‐pituitary adrenal (HPA) axis is activated which stimulates the release of stress hormones called glucocorticoids into the blood stream. Studies on early‐life stress have shown a glucocorticoid dependent vulnerability towards late‐life inflammation. However, adolescence may be a more critical period for stress‐induced vulnerability for late‐life neurodegenerative diseases given that adolescents experience longer circulating levels of glucocorticoids following stress exposure and greater stress responsivity. Additionally, sex is an important biological variable because there are sex differences in AD prevalence and stress vulnerability with women being affected more than men. We hypothesized that adolescent stress would exacerbate AD pathology later in life and that this effect will be stronger in females.MethodMale and female WT and Tg‐SwDI mice underwent a chronic social stress paradigm during adolescence (1‐1.5 months of age). The paradigm consists of alternating social isolation and change in group composition for 20 days. Mice were assessed longitudinally at 2, 4, and 6 months of age for anxiety‐like behavior, cognitive function, and social behavior. Brains were collected at 6 months of age to assess neuropathology.ResultAdolescent stress had an age‐dependent effect on anxiety‐like behavior and cognitive function whereby mice who experienced adolescent stress had greater anxiety and worse cognitive function as they aged compared to control mice. Further, there were sex differences in both anxiety‐like behavior and social behavior at 6 months of age, with females showing greater anxiety‐like behavior and social avoidance compared to male mice. Neuropathology assessments are ongoing.ConclusionThis data suggests that adolescent stress may exacerbate AD pathology later in life, with females being more susceptible than males to these effects. This data is in line with clinical studies showing that females are more likely to develop AD and suffer from anxiety disorders.
Exploring Neural Correlates of Cognitive Awareness across the Alzheimer’s Disease Continuum: A Multimodal Study
Authors: Cacciamani Federica , Houot Marion , Thibeau‐Sutre Elina , du Montcel Sophie Tezenas , Migliaccio Raffaella 
Published: January 2025

AbstractBackgroundAnosognosia, a hallmark of Alzheimer’s disease (AD), manifests as a gradual decline in disease awareness, yet its neural correlates remain unclear. This study investigates how amyloid accumulation, glucose hypometabolism and cortical atrophy relate to cognitive awareness across the AD continuum. Both the pathological processes and the brain regions involved were studied.MethodsWe included 263 cognitively‐normal (CN) individuals, 411 with mild cognitive impairment (MCI), and 111 diagnosed with AD from the ADNI cohort, with a mean±SD of 5.4±2.4 visits (Table 1). Awareness was assessed using the subject‐informant discrepancy on the ECog questionnaire, ranging from –3 to 3, with lower values indicating lower awareness. Neuroimaging measures included amyloid load assessed with 18F‐AV‐45‐PET, glucose metabolism with FDG‐PET, and cortical thickness with T1‐MRI, across the entire brain segmented into 86 regions of interest (ROIs) using FreeSurfer. In multivariate linear mixed models, we modeled the awareness index with baseline amyloid load, metabolism, and cortical thickness in each ROI. Models were adjusted for sex, age, education, and depression. We also factored in interactions between these variables and time, while correcting for multiple comparisons.ResultsResults are presented in Figure 1. In individuals with AD: awareness was lower at baseline than in the other groups (p<0.001); it decreased over time (β±SE = ‐0.21±0.04; p<0.001); and lower awareness was associated with lower education (β±SE = 0.07±0.02, p = 0.004) and reduced left posterior cingulate metabolism (standardized β±SE = ‐0.24±0.07, p = 0.042). In participants with MCI: awareness was lower at baseline than in CN participants and higher than in AD (all p<0.001), and it decreased over time (β±SE = ‐0.07±0.01, p<0.001); greater decline in awareness was associated, first, with higher baseline amyloid in all ROIs except the hippocampus, parahippocampus, right posterior cingulate and right amygdala (all p<0.001); second, with decreased left posterior cingulate metabolism (standardized β±SE = ‐0.14±0.04, p = 0.006); third, with greater atrophy at baseline in the bilateral hippocampi, amygdala, and superior occipital gyri (all p<0.001). In CN individuals, we observed no significant associations (all p>0.05).ConclusionAll three processes were associated with cognitive awareness, exhibiting distinct patterns across different groups. Additionally, our findings revealed widespread involvement of multiple ROIs.
Sleep Apnea in Arthritis Patients: A Multifactorial Analysis in the National Alzheimer’s Coordinating Center Cohort
Authors: Irfan Bilal , Pal Subhamoy , Reader Jonathan M , Giordani Bruno 
Published: January 2025

AbstractBackgroundSleep apnea, a common sleep disorder, has been associated with various health conditions, including arthritis. This study investigates the relationship between sleep apnea and arthritis, examining how demographic and clinical characteristics impact this association. There are several interrelations between sleep apnea and arthritis, one of which may be attributed to systemic inflammation and oxidative stress pathways commonly activated in both conditions. There is an increasing prevalence of both conditions in aging populations, with potential implications for clinical practice and patient management.MethodThe study utilized logistic regression analysis to assess the presence of sleep apnea in a sample of 46,268 participants from NACC ADRC first assessments with UDSv3, considering arthritis, age, race (white/non‐white), Hispanic origin, sex, education, and diagnosis (Alzheimer’s Disease [AD], Mild Cognitive Impairment [MCI], Cognitively Unimpaired). The analysis aimed to understand the likelihood of sleep apnea occurrence in relation to these factors.ResultThe mean age of participants was 71.33 years (57% female). Arthritis was significantly associated with sleep apnea (aOR = 1.91, 95% CI: 1.75, 2.09, p < 0.001). Age showed a borderline non‐significant influence (aOR = 1.00, p = 0.086). Female sex was less likely to be associated with sleep apnea compared to males (aOR = 0.40, 95% CI: 0.37, 0.44, p < 0.001). Educational attainment showed a slight positive correlation with sleep apnea presence (aOR = 1.02, p = 0.018). In terms of cognitive diagnosis, MCI and AD were associated with higher odds of sleep apnea compared to normal cognition (MCI: aOR = 1.33, p < 0.001; AD: aOR = 1.13, p = 0.026). MCI was associated with higher odds of sleep apnea compared to AD (aOR = 1.18, p = 0.004). Race and Hispanic origin did not show significant associations with sleep apnea.ConclusionThe study highlights a significant association between arthritis and sleep apnea. Sex differences and educational level also play a role in the likelihood of developing sleep apnea among arthritis patients. These findings suggest a need for targeted screening and management strategies for patients with both sleep apnea and arthritis, particularly considering sex and cognitive status.
Comprehensive Characterization of Conformational Dynamics in Risk and Resilience Alleles of Apolipoprotein E for Alzheimer’s Disease using Long‐Time Scale Molecular Simulations And Graph Neural Networks
Authors: Martin William , Cheng Feixiong 
Published: January 2025

AbstractBackgroundApolipoprotein E (ApoE) is the primary cholesterol and lipid transporting apolipoprotein in the central nervous system (CNS) and is the greatest genetic risk factor for Alzheimer’s Disease (AD). There are three main isoforms differing by single amino acid changes: ε3 is “neutral”, ε4 is “risk” (Cys112Arg), and ε2 is “resilience” (Arg158Cys). Rare forms (Christchurch, Jacksonville) have also been proposed as resilience alleles, while an ε4‐like allele (with Arg61Thr) is present in non‐human primates without AD risk. To date, only a single mutated NMR structure of full‐length ε3 in a closed conformation exists, leaving unanswered questions regarding conformational differences between isoforms. Additionally, nearly all experimental data for ApoE considers multimeric structures as opposed to the biologically relevant monomer.MethodHere, we have integrated a graph representation of long‐time scale molecular simulation data with neural networks to generate reversible Markov state models. Our method utilizes multiple replicates of long‐timescale (six replicates of 15 µs per isoform, 540µs in total) to generate 200 starting conformations per isoform, each of which was simulated in triplicate for and additional 1 microsecond (600 µs per isoform). In total, 4.14 milliseconds of simulation across 6 isoforms were generated. We use Markov state models generated using GraphVAMPNets (a deep neural network utilizing graphs as the input data) in conjunction with DeepMSM, elucidating key macrostates for each isoform which may dictate the differences in conformation, informing the risk versus resilience potential. Finally, we integrated CoVAMPNet, a framework for directly comparing macrostates from different datasets.ResultWe have identified conformational differences between comparable macrostates which may inform differences in risk or resilience across the isoforms. This elucidation is a result of our integration of protein energy networks with molecular modeling, and may inform the development of future therapeutics targeting ApoE in AD. Mapping of macrostates to each other and comparing mean first passage times indicates potential risk and resilience states, with ε4 having lower transition times into a specific state and ε2 having a particularly stable state.ConclusionWe have identified putative risk or resilience conformational states in APOE, which may have implications for therapeutic discovery.
Development of stem cell‐derived microfluidic models of the blood‐brain barrier in Alzheimer’s disease
Authors: Takeuchi Lily E , Simmons Craig A 
Published: January 2025

AbstractBackgroundDrug discovery efforts in neurological diseases, such as Alzheimer’s disease (AD), have had particularly poor outcomes due to the lack of models that capture the cerebral vasculature. There is an unmet need to develop models that capture the physiological challenge of overcoming the blood‐brain barrier (BBB) and impacts of blood flow‐induced shear stress. In this work, we use a microfluidic platform to model the cerebral vasculature in familial AD (fAD) using patient‐derived brain endothelial‐like cells (BECs) and neurons.MethodStem cells derived from a patient with fAD (PSEN‐2 N141I) and an unaffected control line were differentiated into BECs and neurons. BECs were cultured statically or exposed to 12 dynes/cm2 of shear stress for 72 hours prior to assessment of barrier permeability using a fluorescent tracer, monocyte adhesion, and efflux transport function using receptor‐inhibition assays.ResultBECs derived from the patient with AD (AD‐BECs) demonstrate reduced capacity for efflux transport by p‐glycoprotein (p‐gp), breast cancer resistant protein (BCRP), and multidrug resistant protein (MRP‐1) compared to controls (fControl‐BECs, **p = 0.0015, ***p = 0.0004, ***p = 0.0002, respectively). Under shear stress conditions, these impairments were not present, suggesting shear stress may play a protective role in maintaining efflux transport function. AD‐BECs show enhanced susceptibility to cytotoxic effects of Aβ42 oligomers between concentrations of 1.25 ∼ 20 µM with cell viability reduced by 19 ∼ 24%. AD‐BECs exhibit increased monocyte adhesion (1.9‐fold; **p<0.01) which was reduced by the application of shear stress in both lines (AD: ***p<0.001; fControl: **p<0.01).ConclusionThis in‐depth characterization of patient‐derived BECs in both static and physiologically relevant shear conditions demonstrates the cerebral vasculature in fAD may be impaired in areas of drug transport, immune cell trafficking, and cytotoxicity, particular in the absence of shear stress as occurs in cerebral hypoperfusion.