bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving dementia phenotype prediction with functional mapping of genetic data in non‐European ancestries
Authors: Fu Mingzhou , Pasaniuc Bogdan , Vossel Keith , Chang Timothy S 
Published: December 2023

AbstractBackgroundMany common genetic variants have been associated with dementia, but their ability to predict dementia prospectively is unknown, especially in non‐European ancestral populations. We sought to optimize dementia risk prediction models with machine learning in individuals of diverse genetic ancestries.MethodSamples were selected from the University of California Los Angeles Health System with their electronic health records (EHRs) and linked genetic data. Dementia phenotype was defined using diagnosis codes and mapped phecodes. Polygenic risk scores (PRSs) were built using summary statistics of different population‐based genome‐wide association studies (GWASs). Independent significant and functionally mapped single nucleotide polymorphisms (SNPs) were identified using the FUMA tool. Logistic regression models were built with 1) APOE status, 2) a single PRS, or 3) multiple PRSs. The model with age and sex only was built as the baseline model. We trained LASSO models to determine dementia risk SNPs from weighted SNP‐level genetic data. We compared the predictive performance of these models after five‐fold cross‐validation with area under precision‐recall curve (AUPRC) and area under receiver operating characteristic (AUC). Finally, identified risk SNPs were mapped to genes for biological interpretation.ResultThere were 975 individuals included in the final Hispanic Latinx American ancestry sample, of which 9.44% (N = 92) were dementia cases. The model with LASSO‐selected functional mapped SNPs from multiple neurodegenerative diseases GWASs outperformed all other genetic risk score models (AUPRC: 0.39, AUROC: 0.87), resulting in a 19.6% increase in AUPRC from the best PRS model, and a 26.9% increase from the baseline model. The best‐performing LASSO model included nine SNPs, mostly located in the 19q13, 4p15, and 17q21 regions. Results of mapped genes not only revealed well‐known risk genes of dementia but identified risk genes from other neurodegenerative diseases.ConclusionWe demonstrated that building genetic risk scores with trans‐ancestry GWAS and selecting potential causal SNPs can be beneficial for dementia prediction in non‐European ancestry populations. Further training using machine learning methods with functionally mapped SNP‐level genetic data showed significant improvement in predictive power compared to PRS models. Genetic risks of multiple neurodegenerative diseases may contribute to the predisposition to dementia.
Blood co‐expression network analysis identifies molecular pathways involved in cognitive resilience
Authors: Tsai Wei , McNiff Caitlin E. , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Nho Kwangsik , Allen Mariet , Heckman Michael G. , Kantarci Kejal , Mielke Michelle M. , Petersen Ronald C. , Saykin Andrew J. , Carrasquillo Minerva M. , Ertekin‐Taner Nilufer 
Published: December 2023

AbstractBackgroundTwo major risk factors of Alzheimer’s disease (AD) are advanced age and the APOE‐ε4 risk allele. However, despite having these risk factors, some individuals escape from developing AD or have slower cognitive decline. In this study we hypothesized that “resilient” individuals, defined as those who remain cognitively normal despite being >80 years‐old and carrying at least one copy of the APOE‐ε4 allele, have concerted changes in their blood transcriptomes that are associated with resilience to AD.MethodWe generated blood RNA‐sequence data from 105 APOE‐ε4 carriers from the Mayo Clinic Study of Aging (MCSA) who remained cognitively normal after age 80 (resilient), or who developed mild cognitive impairment (MCI) or AD (non‐resilient). Weighted gene co‐expression network analysis (WGCNA) was performed to evaluate the association of the blood co‐expression network with primary phenotypes of resilience and memory scores. To validate our findings, we constructed a consensus co‐expression network using both MCSA and a replication cohort of blood microarray data from 91 Alzheimer’s Disease Neuroimaging Initiative (ADNI) study participants who had a similar demographic profile. We annotated the consensus modules for their enrichment of cell types, biological processes, genes within previously published genome‐wide significant (GWS) AD‐associated loci, and genes that reside in consensus modules built from seven brain regions across three different autopsy cohorts. To identify genetic variants regulating blood consensus module co‐expression, we performed module quantitative trait locus (modQTL) analysis.ResultWe found co‐expression modules significantly (q<0.05) correlated with the memory phenotype, logical memory delayed recall, across both MCSA and ADNI cohorts. Some of these modules were enriched with blood cell types and biological processes, including telomere maintenance, mitochondrial functions, and immune response. We found 1 module significantly (q<0.05) enriched with genes near GWS AD‐associated loci and 4 modules with genes in brain consensus modules. Lastly, we found 8 modQTLs significantly (Bonferroni‐p<0.05) associated with the co‐expression of 5 different modules.ConclusionWe identified blood co‐expression modules, biological pathways and specific genetic variants associated with cognitive resilience in the presence of AD risk factors. This study provides novel insights into the potential role of peripheral blood in the development of and resilience to AD.
Deep trans‐omic network fusion for altered functional interactions underlying Alzheimer’s Disease
Authors: Xie Linhui , Raj Yash , Varathan Pradeep , He Bing , Nho Kwangsik , Salama Paul , Saykin Andrew J. , Yan Jingwen 
Published: December 2023

AbstractBackgroundMulti‐omic data like genotype, gene expression and protein expression have been increasingly explored in post‐GWAS era to interpret GWAS findings and to gain more insight of the Alzheimer’s disease (AD) mechanism. However, each ‐omics data type is usually examined individually and identified genetic variations, genes and proteins are not necessarily functionally related.MethodWe used GWAS genotype, RNA‐Seq gene expression, and protein expression data from 133 subjects of ROS/MAP Project for original study and 121 subjects of Mount Sinai Brain Bank (MSBB) for replication (Fig. 1a). The multi‐omic data pre‐processing steps were shown in Fig. 1b. We proposed a new interpretable deep neural network MoFNet, extended from Varmole [1], to jointly model the prior knowledge of functional interactions using ROS/MAP cohort (Fig. 1c). It aimed to identify a subnetwork of functional interactions from prior knowledge that are both predictive of AD and evidenced by multi‐omic data. Particularly, prior functional interaction network was embedded into the architecture of MoFNet in a way that it resembles the information flow from DNA to gene and protein.ResultThe proposed model MoFNet significantly outperformed all other state‐of‐art classifiers when evaluated using multi‐omic data from ROS/MAP cohort (Table 1). It yielded three major multi‐omic sub‐networks related to innate immune system, clearance of mis‐folded proteins, and neurotransmitter release respectively (Fig. 2a). One subnetwork includes all the major members of the SNARE complex, an essential mediator of synaptic vesicle fusion. Majority of our identified genes/proteins are related to synaptic activities in neuronal, astrocyte and microglial cells. Differential expression analysis show MoFNet returned more genes and proteins due to functional connections (Fig. 2b). Around 50% of these findings were replicated in another independent cohort (MSBB).ConclusionOur identified gene/proteins are highly related to synaptic vesicle function. Altered regulation or expression of these genes/proteins could cause disruption in neuron‐neuron or neuron‐glia cross talk and further lead to neuronal and synapse loss in AD. Further investigation of these identified genes/proteins could possibly help decipher the mechanisms underlying synaptic dysfunction in AD, and ultimately inform therapeutic strategies to modify AD progression in the early stage. [1] Nguyen et al., Bioinformatics, 2021.
AMYLOID‐Β AND PHOSPHORYLATED‐TAU ACCUMULATION IN RETROSPLENIAL CORTEX OF YOUNG ALZHEIMER’S MODEL
Authors: Mondragón‐Rodríguez Siddhartha 
Published: December 2023

AbstractBackgroundOur aim in the present study was to evaluate molecular and functional alterations in the retrosplenial cortex (RSC) of very young Alzheimer’s transgenic mice (3xTg‐AD). The RSC is a cortical area that functions as a key component of the core network of brain regions involved in cognitive functions such as episodic memory, navigation, and planning.MethodElectrophysiology: Local field potentials were recorded using borosilicate electrode (2‐6 MΩ). Integrated theta‐band power was calculated in 5 s binds over a period of 2‐10 min and the mean spectrum was taken as the grand mean of each animal.Immunohistochemistry: For immunofluorescence, antibodies: pS396 and BAM10 were used. The brain areas were visualized using an epifluorescence microscope (Axioplan2, Zeiss).ResultOur results show significant accumulation of intracellular amyloid‐β (Aβ) and hyperphosphorylated tau (pTau) in principal neurons from 1‐month‐old 3xTg‐AD mice, which correlates with GSK3β activation and tau phosphorylation at serine 396. Coincidently, oscillatory activity from the RSC is altered in the young 3xTg‐AD mice. Specifically, we found that theta frequency is significantly higher in the transgenic animals.ConclusionDespite the wide consensus that Aβ deposition in a variety of AD transgenic mice, including 3xTg‐AD, is detected after several months of age, this study shows the first evidence of intracellular Aβ accumulation in pyramidal cells as early as 30 days of age, which does not seem to be related to any cognitive compromise. Thus, early Aβ and pTau accumulation was correlated with altered oscillatory activity from the RSC. In sum, our results indicate that very early accumulation of intracellular Aβ may impact the excitability of the RSC network, possibly due to changes in pTau throughout GSK3β activation.
Neuropsychological Profile of Internal Frontal Hyperostosis
Authors: Oliveros‐Cid Antonio , Lorente Victoria Celorrio , Oliveros‐Juste Antonio , Cimorra Belen Delgado , Luque Laura Cano , Lopez Maria Angeles Cid , Martinez Esther Sierrra , Moreno Lisbed Rondon , Izaguerri Cristina 
Published: December 2023

AbstractBackgroundIn 1765 Giovanni Morgagni described internal frontal hyperostosis syndrome (IFH), obesity and hirsutism. Stevart (1928) and Morel (1930) added the presence of neurological and neuropsychiatric involvement, constituting the definition of Morgagni‐Stewart‐Morel Syndrome (MSM). There are cases of HFI with absence of the rest of symptoms.MethodClinical, neuropsychological and neuropsychiatric evaluation of 5 patients treated for cognitive and behavioral impairment in whom neuroimaging neuroimaging showed internal frontal hyperostosis, apparently of sufficient entity to be associated with frontal lobe compression. Independent evaluation of the rest of the clinical and and family history that could indicate the presence of the constellation of constitutive symptoms of MSM.ResultThe neuropsychological battery showed as fundamental findings: depressive mood, attentional deficit, deterioration of working and recent memory, loss of concentration. No productive psychotic symptoms. Difficulty in complex tasks or complex skills. Anhedonia. No obsessive or compulsive symptomatology, nor anxiety as a predominant symptom. Irritability and irascibility. Mnesic process of inactive profile, difficulty in the change of mnesic strategy or language, or inhibition of irrelevant stimuli, problems with calculation, reasoning, sequencing or mental organization. Reduced verbal and non‐verbal fluency and disordered self‐regulation. Attention was drawn to the discordance between the significant functional impairment of the patients and the relatively preserved performance on neurocognitive battery.ConclusionThe presence of psychiatric and neurocognitive symptomatology associated with HFI has a characteristic profile, a varied constellation of deficits attributable to frontal lobe dysfunction, but should be actively investigated, because of its difficult until it significantly affects the patient’s performance.
Understanding social network and cognitive function among Korean immigrant older adults in the United States
Authors: Han Hae‐Ra ,   PLAN trial team
Published: December 2023

AbstractBackgroundSocial networks provide benefits to older adults, including some positive impact on cognitive health. Immigrant older adults with limited English proficiency in the United States (US) may experience the disruption of social network change resulting from their relocation compounded with language barriers. Despite the central role of social networks in older adults’ cognitive function, little information is available about actual social network size among immigrant older adults in the US and how social network sizes are associated with their cognitive status.MethodKorean American (KA) older adults represent one of the fastest growing, yet some of the most vulnerable groups in the US due to their limited English proficiency. PLAN—Preparing health aging through Dementia literacy And Navigation—is an ongoing, multi‐site clinical trial involving KA older adults (65+ years) with probable dementia with a goal of promoting their linkage to dementia care. Potential participants go through cognitive screening using Mini‐Mental State Exam (MMSE) to confirm eligibility. Part of the screening process involves a survey about social network using Lubben Social Network Scale‐6 as availability of a caregiver is part of eligibility criteria. Using eligibility screening data, we investigated social network among community‐dwelling KA older adults and its association with MMSE status after controlling for age, sex, and education.ResultA total of 747 KA older adults (mean age = 77 years, 28% male, and 61% ≤high school) were included in the analysis. More than one third (35%) of the sample had a score <12 on the Lubben scale, indicating being “at risk for social isolation.” Logistic regression analysis revealed that KA older adults who were at risk for social isolation had more than twice higher odds (adjusted odds ratio = 2.007, p = 0.002) of being MMSE positive (i.e., cognitive decline) than those who were not, after controlling for age, sex, and education.ConclusionSocial network analyses have potential to present much needed information in relation to older adults’ health status. Our findings suggest the urgent need for social support resources in this socially disadvantaged group of immigrant older adults. Future research should investigate effective strategies to enable access to the resources of wellness in the population.
Depression is associated with dementia and accelerated cognitive decline in African Americans
Authors: Lachner Christian , Craver Emily C , Crook Julia E. , Lucas John A. , Ferman Tanis J , Graff‐Radford Neill R. , Day Gregory S. 
Published: December 2023

AbstractBackgroundAfrican Americans (AA) represent 12% of the United States population ≥65 years‐old, but 19% of persons with dementia. Inequalities in social determinants of health may influence access to healthcare resources contributing to increased dementia risk. Modifiable risk factors, including vascular risk factors and depression, may contribute up to 40% of dementia risk and are overrepresented in AA. Accordingly, risk factor modification in AA may improve disparities and decrease dementia risk.MethodDementia risk factors were evaluated in community‐dwelling AA (n = 261) and non‐Hispanic White (NHW; n = 193) participants who completed ≥2 research visits in studies of memory and aging at the Mayo Clinic Florida Alzheimer Disease Research Center. The association between modifiable risk factors and cognitive impairment (global Clinical Dementia Rating® [CDR] ≥0.5), and rates of decline in impaired participants (measured using the CDR Sum‐of‐Boxes; CDR‐sb) were compared between AA and NHW, while controlling for demographics, APOEe4 status, and Area Deprivation Index.ResultModifiable dementia risk factors were common in AA and NHW participants. The ADI was higher in AA denoting greater socioeconomic and environmental deprivation [7.8 (2.3) vs. 4.0 (2.1); p<0.001]. History of stroke/transient ischemic attack (OR, CI95% = 2.52, 1.08‐5.83) was associated with an increased odds of dementia in AA participants only, while depression was associated with an increased odds of dementia in both AA (3.10, 1.52‐6.30) and NHW (3.46, 1.14‐10.48) participants. Moreover, depression (β, CI95% = 1.55, 0.5‐2.6), p = 0.004) was associated with a faster rate of decline (CDR‐sb) in cognitively impaired AA participants. AA participants with depression were disproportionately less likely to report use of antidepressant medications than NHW counterparts (40/45, 89% vs. 21/44, 48%); p<0.001).ConclusionModifiable risk factors associated with dementia were common in AA and NHW participants. Depression was associated with dementia in both AA and NHW but uniquely associated with an accelerated rate of cognitive decline in AA participants. Disparities in use of antidepressant medications may contribute to these differences. Optimizing depression treatment in AA communities may improve cognitive trajectories and dementia risk in this population.
Apolipoprotein E polymorphism‐dependent effects on cellular function
Authors: Beyer Brittney A , Levine Zachary 
Published: December 2023

AbstractBackgroundWe have used a combination of cell‐based and biophysical approaches to investigate mechanisms by which apolipoprotein E (APOE) isoforms induce either protective or Alzheimer’s Disease (AD)‐associated pathological features.MethodAPOE polymorphism‐driven phenotypic and functional changes were investigated in both primary human astrocytes and central nervous system (CNS) cell types generated from a set of APOE isogenic hiPSC lines (APOE KO, E2, E3, E4). Using fluorescently‐labeled APOE, the transport of E2, E3 and E4 isoforms were tracked in live cells and changes in organelle co‐localization was assessed. Lipoprotein particles were isolated from conditioned media to investigate APOE polymorphism‐specific alternations in the assembly and secretion of high‐density lipoprotein (HDL) particles.ResultWe have identified APOE polymorphism‐specific changes in subcellular localization of APOE that are correlated with changes in cellular function, as well as the function of APOE as a major transporter of lipids and cholesterol in the brain.ConclusionOur results provide mechanistic insight into structure:function relationship of APOE in the context of pathological and protective isoforms.
Effect of disease‐associated variants in TREM2 on splicing and gene dosage
Authors: Korvatska Olena , Kiianitsa Kostantin , Lukes Maria E , Bird Thomas D. , Raskind Wendy H 
Published: December 2023

AbstractBackgroundLoss‐of‐function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu‐Hakola disease (NHD) and behavioral variants of frontotemporal dementia (FTD), while heterozygous variants increase risk of late onset Alzheimer’s disease (AD) and FTD. In over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level, via premature termination codons or via aberrant splicing. The remaining ones are missense variants thought to inactivate the protein; however, the underlying pathogenic mechanism is less clear. In this work we tested whether disease‐associated TREM2 variants may contribute to the pathology via altered splicingMethodSpliceAI prediction algorithm was used to screen 56 disease‐associated/risk‐modifying variants for potential effect on splicing. Variants scored by SpliceAI were tested in the splicing reporter assay with full‐length TREM2. Constructs with the common TREM2 variant or the spliceogenic SNP allele were nucleofected into THP‐1, HMC3 and BV2 cell lines. qRT‐/RT‐PCR and western blots were used to quantify the effect of variants at the transcript and protein levels. Nanostring nCounter analysis was used to measure TREM2 RNA in brains of NHD patients who carried spliceogenic variants.ResultWe demonstrated that multiple variants causative for NHD or associated with AD/FTD affect gene splicing reduced dosage of functional transcript and protein.ConclusionOur findings point to the complex character of pathogenicity of TREM2 variants, in which effects on post‐transcriptional gene regulation and protein function are often combined. This hidden layer of complexity necessitates inclusion of computational and experimental analyses of splicing and mRNA processing for better understanding of genetic variation in disease.
A transcriptome‐wide analysis of Alzheimer’s disease brain during systemic inflammation
Authors: Pegoraro Giulia , Smith Rebecca G. , MacBean Lachlan Ford , Smith Adam R. , Boche Delphine , Pishva Ehsan , Lunnon Katie 
Published: December 2023

AbstractBackgroundThe onset and progression of Alzheimer’s disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, many AD sufferers ultimately die with a systemic infection, and infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients. One of the aims of this study is to investigate the molecular mechanisms involved in the CNS response to systemic infections in AD through the analysis of gene expression changes.MethodThe cohort of patients selected for the study is composed of 238 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 68 samples affected by AD and 55 controls, all of whom died with an infection, and 62 AD patients and 53 controls who did not have an infection at the time of the death. The infections included in the analysis consists of respiratory infections (i.e. pneumonia), urinary and chest infections. Following RNA sequencing, a weighted gene correlation network analysis (WGCNA) and pathway enrichment analysis were performed.ResultThe results from WGCNA show a module of particular interest with a correlation with both AD and respiratory infections, which represent most of the cases of infection. The pathway enrichment analysis performed on the genes composing this module identified several relevant biological pathways. Among the ten most significant pathways, part of them is involved in immune responses, such as “leukocyte activation involved in immune response” and “cell activation involved in immune response”.ConclusionThis analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include repeating the analysis focusing on respiratory infections only, to examine if this source of heterogeneity is limiting our findings. Ultimately this data will be combined with miRNA sequencing and DNA methylation data from the same individuals, the work for which is ongoing.