A polygenic risk score for Alzheimer’s disease constructed using APOE-region variants has stronger association than APOE alleles with mild cognitive impairment in Hispanic/Latino adults in the U.S.

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: Aug. 30, 2023

Abstract Introduction Polygenic Risk Scores (PRSs) are summaries of genetic risk alleles for an outcome. Methods We used summary statistics from five GWASs AD to construct PRSs in 4,189 diverse Hispanics/Latinos (mean age 63 years) the Study Latinos-Investigation Neurocognitive Aging (SOL-INCA). assessed PRS associations with MCI combined set people and subgroups, when including excluding APOE gene region. also independent dataset Mass General Brigham Biobank. Results A simple sum 5 (“PRSsum”), each constructed based on a different GWAS, was associated (OR = 1.28, 95% CI [1.14, 1.41]) model adjusted counts - $$\epsilon 2$$ ϵ 2 4$$ 4 alleles. Associations single-GWAS were weaker. When removing SNPs region PRSs, association PRSsum weaker 1.17, [1.04,1.31] adjustment alleles). In all analyses, not MCI. Discussion is Hispanic/Latino older adults. Despite no MCI, stronger Thus, variants than classic may be important predictors

Language: Английский

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KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2748 - 2748

Published: Oct. 14, 2021

Neurogenesis decreases in Alzheimer’s disease (AD) patients, suggesting that restoring the normal neurogenic response could be a modifying intervention. To study mechanisms of pathology-induced neuro-regeneration vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report Kynurenic acid (KYNA), metabolite amino tryptophan, negatively regulates stem cell (NSC) plasticity adult brain through receptor, aryl hydrocarbon receptor 2 (Ahr2). The production KYNA suppressed after amyloid-toxicity reduction levels Kynurenine transferase (KAT2), key enzyme producing KYNA. NSC proliferation enhanced by antagonist for Ahr2 and reduced with agonists or A subset Ahr2-expressing NSCs do not express other regulatory receptors such as il4r ngfra, indicating ahr2-positive constitute new progenitors are responsive amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) three late onset Alzheimer (LOAD) autopsy cohorts, also found several genes components metabolism AHR signaling differentially expressed LOAD, strong link between KYNA/Ahr2 axis neurogenesis LOAD.

Language: Английский

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MU-BRAIN: MUltiethnic Brain Rna-seq for Alzheimer INitiative

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

Abstract Alzheimer’s Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays crucial role in unraveling the disease’s etiology progression. Transcriptome data across ethnic groups lack, negatively impacting equity intervention research. We employed 565 brains six U.S. brain banks ( n= 399 non-Hispanic Whites, n =113 Hispanics, 12 African Americans) to generated bulk RNA sequencing from prefrontal cortex. sought identify cross-ancestry ancestry-specific differentially expressed genes (DEG) Braak stages, adjusting for sex, age at death, quality metrics. further validated our findings using Religious Orders Study/Memory Aging Project (ROS/MAP; 1,095) performed metanalysis 1,660). conducted Gene Set Variation Enrichment analysis (GSVA; GSEA). machine-learning approach phenotype prediction prioritization construct polytranscriptomics risk score (PTRS) splitting sample into training testing sub-samples, either randomly or by ethnicity (“ancestry-agnostic” “ancestry-aware”, respectively). Lastly, we top DEG single-nucleus (snRNAseq) data. identified several associated with staging: AD-known VGF P adj =3.78E- 07) ADAMTS2 ad j =1.21E-04) were consistently statistical models, ethnicities, replicated ROS/MAP. Genes heat shock protein HSP ) family, e.g. HSPB7 =3.78E-07), Ethnic-stratified analyses prioritized TNFSF14 SPOCD1 as Hispanics DEG. GSEA highlighted “ Alzheimer disease ” =4.24E-06) TYROBP causal network microglia =1.68E-08) pathways. Up- down-regulated enriched pathways (e.g. Immune response activation signal pathways” , Vesicle-mediated transport synapse ”, cognition ”). Ancestry-agnostic ancestry-aware PTRS effectively classified (AUC=0.77 0.73 respectively) snRNAseq genes, including downregulated neurons; =1.1 E-07). This is largest diverse AD transcriptome post-mortem tissue, knowledge. perturbated expressions resulting cross- ethnic-specific findings, ultimately highlighting diversity within pathogenesis. The latter underscores need an integrative personalized studies.

Language: Английский

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Dexmedetomidine mitigates neuroinflammation in an Alzheimer's disease mouse model via the miR-204-3p/FBXL7 signaling axis

Brain Research, Journal Year: 2023, Volume and Issue: 1822, P. 148612 - 148612

Published: Sept. 29, 2023

Language: Английский

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Donor-Specific Transcriptomic Analysis of Alzheimer's Disease-Associated Hypometabolism Highlights a Unique Donor, Ribosomal Proteins and Microglia

eNeuro, Journal Year: 2020, Volume and Issue: 7(6), P. ENEURO.0255 - 20.2020

Published: Nov. 1, 2020

Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low-glucose utilization in regions of the cerebral cortex marks early AD. To identify these regions, we conducted a voxel-wise meta-analysis previous studies with positron emission tomography that compared AD patients healthy controls. The resulting map hypometabolism posterior cingulate, middle frontal, angular gyrus, and inferior temporal regions. Using Allen Human Brain Atlas, identified genes show spatial correlation across between their expression this hypometabolism. Of six brains one demonstrated strong gene Previous neuropathological assessment brain from 39-year-old male noted neurofibrillary tangle entorhinal cortex. transcriptomic data, estimate lower proportions neurons more microglia hypometabolic when comparing donor’s other five donors. Within single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which encode primarily cytosolic ribosome proteins, are highly expressed Analyses human mouse data increases progressively AD-associated states microglial activation. In addition, involved cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, vacuole sorting associated map. These suggest disruption life cycle neuroimmune Taken together, our molecular characterization reveals link to may be relevant preclinical stages

Language: Английский

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Systematic review and meta-analysis of bulk RNAseq studies in human Alzheimer's disease brain tissue

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 8, 2024

Abstract Objective To systematically review and meta-analyze bulk RNA sequencing studies comparing Alzheimer’s disease (AD) patients with controls in human brain tissue, assessing study quality identifying key genes pathways. Methods We searched PubMed, Web of Science, Scopus on September 23, 2023, for using RNAseq primary tissue from AD controls. Excluded were non-primary re-analyses without new data, limited types gene panels. Quality was assessed a 10-category tool. Meta-analysis used high-quality datasets. Results From 3,266 records, 24 met criteria. found 571 differentially expressed (DEGs) temporal lobe 189 frontal lobe; overlapping pathways included "Tube morphogenesis" "Neuroactive ligand-receptor interaction." Limitations Study heterogeneity data tables constrained the review. Conclusions Rigorous methods are vital transcriptomic studies. Findings enhance understanding changes, aiding biomarker therapeutic development. Registration PROSPERO (CRD42023466522).

Language: Английский

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Reported race-associated differences in control and schizophrenia post-mortem brain transcriptomes implicate stress-related and neuroimmune pathways

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Nov. 18, 2024

Background The molecular mechanisms underlying racial disparities in schizophrenia (SCZ) illness courses and outcomes are poorly understood. While these differences thought to arise partly through stressful social gradients, little is known about how reflected the brain, nor they might underlie disparate psychiatric outcomes. Methods To better understand neuro-molecular correlates of SCZ, their overlap, we analyzed post-mortem dorsolateral prefrontal cortex (DLPFC) RNAseq data from two racially diverse cohorts CommonMind Consortium (235 reported Black 546 White, 322 SCZ cases 459 controls) using differential expression gene set variation analyses. Results We observed brain that were consistent across race. A combined mega-analysis identified 1,514 genes with (DE) between race groups after accounting for diagnosis other covariates. Functional enrichment analyses upregulation involved stress immune response, highlighting potential role environmental groups. In a race-by-diagnosis interaction analysis, no individual passed statistical significance. However, 109 sets showed statistically significant differences, implicating metabolic pathways. Conclusion Our results suggest uniquely perturbed identify several candidate pathways associated race-dependent manner. underscore importance cohort ascertainment capture population-level pathogenesis.

Language: Английский

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A Molecular Basis of Human Brain Connectivity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 24, 2023

Neuroimaging is commonly used to infer human brain connectivity, but those measurements are far-removed from the molecular underpinnings at synapses. To uncover basis of we analyzed a unique cohort 98 individuals who provided neuroimaging and genetic data contemporaneous with dendritic spine morphometric, proteomic, gene expression superior frontal inferior temporal gyri. Through cellular contextualization morphology, identified hundreds proteins related synapses, energy metabolism, RNA processing that explain between-individual differences in functional connectivity structural covariation. By integrating genetic, molecular, subcellular, tissue levels, bridged divergent fields biology identify connectivity.

Language: Английский

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