bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overview and Application of Intrasubject Variability in ADRD Research
Authors: Malek‐Ahmadi Michael H. 
Published: January 2025

AbstractIntrasubject variability is an important, but often overlooked, measure that has shown to be predictive of important clinical outcomes in ADRD research. Intrasubject variability is often quantified using the intrasubject standard deviation (ISD) that is derived from longitudinal measures or cross‐sectional observations from similarly scaled variables. This talk will begin with an overview of ISD and its application in both longitudinal and cross‐sectional analyses. For longitudinal analyses, ISD can be an important measure of normative performance variability on cognitive measures which can better inform clinicians on what normative trajectories for cognitive tests might be. An example using longitudinal data for the Montreal Cognitive Assessment (MoCA) will demonstrate how the ISD can be used quantify normative variability of longitudinal cognitive performance. The second part of this talk will discuss how ISD is used in cross‐sectional analyses of neuropsychological data. Specifically, how ISD is used to characterize the concept of dispersion which quantifies the inconsistency of between‐domain cognitive performance. Several studies have indicated that cognitive dispersion predicts incident cognitive decline and is associated with AD pathology which highlight the utility ISD may have in characterizing preclinical AD. An additional example using data from a complex motor task will show how the ISD of repeated task trials can differentiate cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD cases. The conceptualization and application of ISD in this talk will set the stage for the other talks in this session that will demonstrate in greater detail how ISD can be used across the AD spectrum.
Mild inhibition of mitochondrial complex I reduces Tau pathology and improves energy homeostasis and synaptic function in human‐derived neurons of LOAD patients
Authors: Nguyen Thi Kim Oanh , Hasan Md Fayad , Trushina Eugenia 
Published: January 2025

AbstractBackgroundDespite recent FDA approvement of disease‐modifying treatments that reduce Aβ, the identification of novel therapeutic strategies that could delay the Alzheimer’s disease (AD) development are needed. We identified and developed novel small molecule compounds that mildly inhibit mitochondrial complex I (MCI). Chronic treatment with a tool compound CP2 in 4 mouse models of familial AD was efficacious protecting against synaptic dysfunction and memory impairment, improving brain energetics and cognitive performance, reducing levels of human pTau and Ab. The objective of this study was to validate efficacy of this approach in a human brain‐like environment to support its translation into clinical trials. Human induced pluripotent stem cells (hiPSC) retain the host’s endogenous AD‐associated genetic alterations and recapitulate multiple hallmarks of late‐onset Alzheimer’s disease (LOAD).MethodUsing pure human induced neurons (iNs) from ApoE4/4‐carrying LOAD patients, we evaluated mitochondrial bioenergetics and morphology using a Seahorse XFe96 flux analyzer and electron microscopy. Axonal trafficking was assessed using MitoTracker Red and live confocal imaging. Immunohistochemistry, quantitative‐PCR, and western blot were carried out to assess changes in the expression of genes and proteins, and cell viability assays were used to perform H2O2 challenge.ResultsCultures of hiPSC‐derived neurons were established using a lentiviral delivery for tetracycline‐inducible expression of NGN2‐GFP fusion gene driven by tetracycline‐responsive promoter. The validation of NGN2‐iNs confirmed the development of mature molecular, cellular, and synaptic properties. LOAD iNs have a significant reduction in the motile mitochondria in axons, increased accumulation of pTau, and altered bioenergetics compared to the control neurons. At CP2 concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, significant reduction of pTau was associated with improved cellular bioenergetics, restored mitochondrial motility, and increased resistance to H2O2 induced oxidative stress.ConclusionLOAD neurons carrying ApoE4/4 alleles recapitulate LOAD phenotype allowing validation of a novel mitochondria‐targeted therapeutics. These data support previous observations in AD mice demonstrating that mild inhibition of MCI induce mild energetic stress with subsequent activation of multifaceted adaptive stress response and neuroprotective mechanisms improving cellular energetics and mitochondrial morphofunction in LOAD human neurons. Further efforts will be focused on the determination of mechanisms of neuroprotection.
BrainNetScore: Enhancing Alzheimer’s disease risk prediction using genetic‐guided brain volumetric phenotype network
Authors: Nam Yonghyun , Woerner Jakob , Jung Sang‐Hyuk , Suh Erica H , Shou Haochang , Shen Li , Kim Dokyoon 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), characterized by significant brain volume reduction, is influenced by genetic predispositions related to brain volumetric phenotypes. While genome‐wide association studies (GWASs) have linked brain imaging‐derived phenotypes (IDPs) with AD, existing polygenic risk scores (PRSs) based models inadequately capture this relationship. We develop BrainNetScore, a network‐based model enhancing AD risk prediction by integrating genetic associations between multiple brain IDPs and AD incidence.MethodUtilizing UK Biobank GWAS summary statistics, we constructed a brain connectivity network from 96 regional brain volume IDPs. This network was expanded into a heterogenous BrainNet graph, incorporating 96 IDPs and 12,043 common variants (SNPs) linked to each IDP. Individual genotype data from independent cohorts, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), were analyzed. Label propagation algorithms generated individualized predicted scores for IDPs, subsequently aggregated into BrainNetScore via logistic regression.ResultBrainNet was built from GWAS summary statistics of 96 brain volume IDPs and individual genotype data for 914 samples (550 AD cases, 364 cognitive normal controls) from ADNI. We compared the predictive performance of BrainNetScore against conventional PRS models (Figure 1). The combined PRS + BrainNetScore model showed a superior average AUC of 0.684 ± 0.034, over PRS only (0.595 ± 0.075) and BrainNetScore only (0.666 ± 0.029) models. Including sex as a covariate and APOE genotypes further enhanced predictive accuracy (0.778 ± 0.043).ConclusionBrainNetScore significantly improves AD risk prediction when combined with PRSs. This highlights the potential of network‐based approaches and comprehensive genetic analysis in developing personalized medicine strategies for AD. Future work should extend this model to diverse populations.
Impact of Abnormal Phosphorylation on the Oligomerization of Tau Repeat R2
Authors: Man Viet H 
Published: January 2025

AbstractBackgroundReversible post‐translational modifications, phosphorylation and dephosphorylation, on tau protein play a critical role in the microtubule (MT) modulation. However, abnormal tau phosphorylation, which occurs in tauopathies such as Alzheimer’s disease (AD), causes the dissociation of tau from MTs. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments (PHF), and insoluble neurofibrillary tangles (NFTs), a hallmark of AD. In this study, we examine the impact of abnormal phosphorylation on monomeric and dimeric structures of tau repeat R2 peptides, which is the essential segment for tau fibrillization and somehow can represent the full‐length tau.MethodsWild‐type tau repeat R2 (wtR2) was taken from an experimental structure of R2‐microtubule complex (PDB code 6CVN). The phosphorylated Ser289 R2 peptide (pS289R2), phosphorylated Ser293 R2 peptide (pS293R2), and phosphorylated Ser289 and Ser293 R2 peptide (pS289+pS293R2) were obtained by phosphorylating the wtR2 at Ser289 and/or Ser293 residues. Extensive replica exchange molecular dynamics simulations using all‐atom force field and explicit solvent were carried out. The structures of R2 monomers and dimers sampled by the simulations were characterized and compared.ResultsFor monomeric conformations, the phosphorylation enhances intramolecular interaction, compactness and β content. For dimeric cases, the phosphorylation increases intermolecular interaction, β‐sheet formation and turn‐coil structural transition. Interestingly, the phosphorylated residue strongly interacts with cations, resulting in a pSer‐cation‐pSer bridge.ConclusionOverall, our results suggest that abnormal phosphorylation at Ser289 and/or Ser293 accelerates the oligomerization of R2 peptides, and consequently it may promote tau aggregation. Furthermore, we also found a pSer‐cation‐pSer bridge formed, thus uncovering the essential role of cation ions in the oligomerization of the phosphorylated R2 repeat. Our findings suggest that phosphorylation at Ser289 and/or Ser293 should be taken into consideration when screening the inhibitors of tau oligomerization.
Loss of GABAB receptor 1 signaling facilitates activation of disease‐associated microglia in the mouse model of Alzheimer’s disease
Authors: LI JIALI 
Published: January 2025

AbstractBackgroundDisease‐associated microglia (DAM), which cluster around Aβ plaques, represent a significant pathological hallmark of Alzheimer’s disease (AD) and play a complex role in influencing neuroinflammation, mediating synapse loss, and participating in the phagocytic clearance of Aβ. Nonetheless, the precise mechanisms by which microglial activation extends beyond the traditional M1 and M2 classifications, encompassing a diverse spectrum of states, especially for DAM, closely intertwined with physiological and pathological conditions under Alzheimer’s circumstances remain elusive.MethodHere, we first combined biochemical techniques and bioinformatic analysis to test and quantify the expression of GABABR1 in both human and mouse AD models. Next, primary microglial cultures, siRNAs, immunohistochemistry, EEG recording and behavior tests were also used for in vitro and in vivo tests of loss of GABABR1 signaling in DAM activation, AD‐like pathology, and sleep impairment in this study.ResultFirstly, we identified that the mRNA expression and protein levels of GABAB receptor 1 (GABABR1) deceased in microglia in the AD brain, especially in DAM compared to resting microglia. Next, we found that Aβ treatment directly lowered GABABR1 expression in microglia. We further found that knocking down GABABR1 in microglia decreased Trem2 expression, which increases the risk of Alzheimer’s pathogenesis. On the contrary, activating GABABR1 in microglia increased C1qb levels. Notably, the administration of 3xTg mice with the GABABR1 agonist cerebrolysin significantly not only restored microglial shape in the mPFC and hippocampus, with fewer branches but also reduced Aβ and hyperphosphorylation of tau levels in the mPFC and hippocampus and improved behavioral deficits and sleep impairment in AD mice.ConclusionOur findings delineate a novel role of loss of the GABABR1 signaling in AD‐associated DAM activation, and elevating GABABR1 activity within DAM holds promise for enhancing microglial structure and function, ultimately alleviating AD‐like pathology and behavioral deficits in the mouse model of Alzheimer’s disease.
Circulating metabolites and risk of incident dementia: A prospective cohort study
Authors: Huang Shu‐Yi 
Published: January 2025

AbstractBackgroundIdentifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions.MethodThis cohort study included a total of 87,885 participants (median follow‐up 9.1 years, 54% female) without dementia at baseline from the UK Biobank. 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer’s disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow‐up. Dementia‐associated metabolites were further analyzed for association with cognitive deficits (N = 87,885) and brain volume (N = 7756) using logistic regression and linear regression.ResultWe identified 26 metabolites associated with incident dementia, of which six were associated with incident AD and five were associated with incident VD. These 26 dementia‐related metabolites were subfractions of intermediate‐density lipoprotein, large low‐density lipoprotein (L‐LDL), small high‐density lipoprotein (S‐HDL), very‐low‐density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L‐LDL (L‐LDL‐C%) was associated with lower risk of AD (HR[95%CI] = 0.92[0.87‐0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10‐6) and hippocampal (β = 0.043, p = 1.93 × 10‐4) volume. Cholesteryl ester to total lipid ratio in L‐LDL (L‐LDL‐CE%) was associated with lower risk of AD (HR[95%CI] = 0.93[0.90‐0.96], p = 1.48 × 10‐4), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S‐HDL (S‐HDL‐CE) were associated with lower risk of VD (HR[95%CI] = 0.81[0.71‐0.93], p = 0.002), but not AD.ConclusionTaken together, circulating levels of L‐LDL‐CE% and L‐LDL‐C% were robustly linked to risk of AD and AD phenotypes, but not with VD. S‐HDL‐CE was associate with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.
Immunodepletion of amyloid‐associated matrisomal proteins reduces Aβ in hiPSC‐derived neurons
Authors: Siciliano Benjamin , Li Qianjin , Ayoubi Riham , Laflamme Carl , Zoeller Elizabeth , Du Yuhong , Fu Haian , Wen Zhexing , Levey Allan I. , Betarbet Ranjita 
Published: January 2025

AbstractBackgroundLarge‐scale unbiased proteomic profiling studies have identified a cluster of 31 proteins co‐expressed with APP, which is termed the matrisome module 42 (M42). M42 is enriched in AD risk genes, including APOE, with mostly secreted proteins that bind heparin, collectively strongly correlate with the burden of brain pathology and cognitive trajectory, and localize to amyloid plaques in AD brain. For these reasons, M42 has been nominated as a novel therapeutic target for enabling drug discovery by our TREAT‐AD Center. Here we immunodeplete several M42 proteins including MDK, SFRP1, HTRA1, QPRT, PTN, and SMOC1 using iPSC‐derived neurons modeling autosomal dominant AD to investigate effects on amyloid production.MethodThe AD‐related APP Swedish mutation (APP KM670/671NL) was introduced into the well‐characterized wildtype control iPSC line (WTC‐11), and programming by the transcription factor neurogenin‐2 (NGN2) was used to generate cultures of high purity excitatory neurons. Inhibition of a collection of M42 proteins with strong correlation with AD endophenotypes was performed by treating neurons with recombinant monoclonal antibodies. Western blot was used to confirm immunodepletion of the secreted protein targets, as well as to measure p‐Tau and total Tau. Enzyme‐linked immunosorbent assay (ELISA) kits specific for human Aβ40 and Aβ42 were used to quantify Aβ species.ResultAβ40, Aβ42, p‐Tau (AT8), p‐Tau (S396), and total Tau, as well as ECM‐associated proteins (MDK, SFRP1, HTRA1, QPRT, PTN, SMOC1) were elevated in neuronal media and cell lysate derived from hiPSCs carrying the APP Swedish mutation relative to WT controls. Immunodepletion of MDK, HTRA1, and PTN reduced Aβ species in neuronal media, while immunodepletion of QPRT increased Aβ species and SFRP1 showed no significant changes.ConclusionhiPSCs with the APP Swedish mutation express and secrete increased levels of several M42 amyloid‐associated proteins as in human AD. Reductions in Aβ species following immunodepletion of MDK, HTRA1, and PTN demonstrate the utility of hiPSC models for probing M42 function and therapeutic potential for AD.
Characteristics of Cognitively Unimpaired Older Adults with Motoric Cognitive Risk
Authors: Large Stephanie E. , Hall James , O'Bryant Sid E. 
Published: January 2025

AbstractBackgroundThe concept of motoric cognitive risk (MCR) combines subjective cognitive concern (SCC) with slowed gait speed. The concept allows for the incorporation of cognitive and functional slowing into a measure of risk assessment. This study explores differences in cognitive functioning in cognitively unimpaired older adults with MCR and those without subjective cognitive concern and without slow gait speed.MethodData from 310 cognitively unimpaired participants from an epidemiological study of aging was collected. The MCR was defined as 1 standard deviation above the mean (controlled for age category and gender) for a four‐meter gait speed walk test and the report of SCC. Then each participant with MCR was matched with an equivalent non‐cognitively impaired participant with no SCC and matching for age, gender, and education. Two participants with MCR were excluded due to not having a match. T‐tests were performed comparing performance on the Geriatric Depression Scale (GDS) and raw scores Wechsler Memory Scale III sub tests Logical Memory I, II and Digit Span, Spanish English Verbal Learning Test (SEVLT) and Trail Making Test Part B.Result308 participants were included in the study with a mean age of 65.04 (8.4), mean education of 11.10 (4.72). The results showed significant differences between the MCR and no MCR groups in on the GDS t (306) = 7.99, p <.001, SEVLT immediate t (306) = ‐5.05, p < .001, SEVLT delayed t (306) = ‐4.84, p <.001, Logical Memory I t (306) = ‐3.79, p <.001, Logical Memory II t (306) = ‐4.18, p < .001, Trail Making Test Part B t (285) = 3.05, p = .003. The digit span sub test was not significant.ConclusionThe study results demonstrate a significant difference in cognitive test performance and depression between those with MCR and without. This supports MCR as a distinct group and potentially as a tool to identify those at risk for later cognitive decline. Future research should examine the relationship between depression and MCR to determine causality, ATN markers in MCR and utility of MCR as a diagnostic category.
Brain microRNAs differentially expressed in age‐related cerebral pathologies
Authors: Luo Tianze , Vattathil Selina M. , Schneider Julie A. , Bennett David A. , Wingo Thomas S. , Wingo Aliza P. 
Published: January 2025

AbstractBackgroundMicroRNAs (miRNAs) are important post‐transcriptional regulators of gene expression, but we have limited insight into their role in age‐related cerebral pathologies. Here, we investigated the association between miRNAs and nine age‐related cerebral pathologies in participants of the ROS/MAP cohorts.MethodMiRNA sequencing was performed on samples from the dorsolateral prefrontal cortex of 617 brain donors from participants of the ROS/MAP cohorts. Following quality control, miRNAs were filtered to 528 verified miRNAs, which were included in the global miRNA differential expression (DE) analysis. A genome‐wide miRNA DE analysis was performed for global Alzheimer’s disease (AD) pathology, Lewy body pathology, TDP‐43, hippocampal sclerosis, arteriolosclerosis, cerebral amyloid angiopathy, cerebral atherosclerosis, gross cerebral infarct, and microinfarct. Two models were tested for each outcome: first, a minimally adjusted model adjusting for potential confounding factors, and a fully adjusted model that further adjusted for co‐existing cerebral pathologies to identify independently associated miRNAs. Gene set enrichment analysis (GSEA) was performed on the targets of DE miRNAs to identify the putative biological pathways underlying these pathologies.ResultWith minimally adjusted models, we found DE miRNAs in global AD pathology, Lewy body pathology, arteriolosclerosis, and cerebral amyloid angiopathy. Extending the analysis to adjust for co‐existing cerebral pathologies, we identified 75 independently associated miRNAs for global AD pathology, 45 for Lewy body pathology, 3 for arteriolosclerosis, and 1 for cerebral amyloid angiopathy at FDR < 0.05. Interestingly, we found miRNAs that are shared between AD hallmark pathologies and other age‐related cerebral pathologies. GSEA of target genes of the independently associated DE miRNAs identified biological pathways related to glutathione metabolism, synaptic functions, cellular transport, and innate immune responses altered in arteriolosclerosis at FDR < 0.05.ConclusionWe identified DE miRNAs in multiple age‐related cerebral pathologies. Our study unveiled shared DE miRNAs between AD hallmark pathologies and other age‐related cerebral pathologies. GSEA results informed putative biological pathways altered in arteriolosclerosis. Collectively, our findings shed light on the role of miRNAs in age‐related cerebral pathologies and establish a basis for future mechanistic studies.
Macroscale structural covariance network reveals the biological mechanisms of neuropsychiatric symptoms in the Alzheimer’s continuum
Authors: Jiang Jiwei , Zhao Kun , Zheng Peiyang , Jiang Shirui , Xu Jun 
Published: January 2025

AbstractBackgroundThe intricate and heterogeneous phenotypes associated with neuropsychiatric symptoms (NPSs) encumber exploration of their role in the neuropathology and underlying biological mechanisms of Alzheimer’s disease (AD) continuum.MethodAn individual‐level Regional Radiomics Similarity Network (R2SN) for 487 patients with AD continuum (376 with NPSs vs. 111 without NPSs) were developed to find the R2SN connections associated with NPSs and refine the subtypes of NPS in the AD continuum. Distinct brain network dysfunction, multimodal neuroimaging burden, and clinical measures/progression of each NPS subtype were analyzed. Gene set enrichment analysis (GSEA) was used to explore the biological mechanisms underpinning the various NPS subtypes and their connections to the biological pathways leading to the AD continuum.ResultThree NPS subtypes were identified based on 300 distinct key R2SN connections. Compared to AD patients without NPS, the first NPS subtype (sNPS) and third NPS subtype (moNPS) exhibited significant opposite pattern of brain connectivity damage, while the second NPS subtype (miNPS) showed minimal differences (Figure 1). Moreover, both sNPS and moNPS subtypes exhibited diminished performance at baseline and rapid decline in the MMSE and MoCA scores, while no statistically significant difference was discerned between the miNPS subtype and those without NPS. Furthermore, both sNPS and moNPS subtypes exhibited reduced regional grey matter volume and cortical thickness in the frontal, temporal, and parietal lobules, while miNPS subtype lacks significant structural brain changes but exhibited higher corrected cerebral blood flow in the inferior frontal gyrus and anterior cingulate cortex, suggesting early compensatory cerebral hyperperfusion (Figure 2). GSEA unveiled the shared and subtype‐specific gene pathways, elucidating each subtype’s unique biological mechanisms associated with the contribution of NPS‐related specific brain connectome dysfunctions to AD progression (Figure 3).ConclusionThis is the first study to identify three distinct NPS subtypes in the AD continuum through a data‐driven approach, bridging the gap in the knowledge on the contributions of NPSs to the onset and development of AD. Our study constitutes a step toward resolving stagnant research progress on NPS management strategies based on clinical symptoms, and offers new insights into precise interventions for these patients.