Multi-omics Analysis And Application Of Mitochondrial Mechanisms In Alzheimer’s Disease

Alzheimer’s disease(AD)is an age-associated progressive neurological disease.The exact pathogenesis of AD is still unknown,and drug development for AD has been repeatedly frustrated in clinical trials over the years.Different theories have been proposed for the cause of AD,and one of the most popular hypotheses currently suggests that mitochondrial dysfunction is an important trigger of AD.This hypothesis suggests that mitochondria have an important role in the early stages of AD disease development and represent a potential new therapeutic strategy.Therefore,targeting mitochondria becomes a promising new therapeutic strategy.Cumulative evidence also suggests that AD is a multifactorial and complex disease,with risk factors such as genetics and environment being particularly important in Late-onset Alzheimer Disease(LOAD),which accounts for94% of all AD cases.Single histology cannot reveal the full etiology and pathology of AD.With the development of multi-omics techniques,researchers are able to explore the global molecular dynamics of the disease in depth at all levels.Therefore,our study systematically reveals the mitochondria-related regulatory mechanisms in different molecular levels of AD from a multi-omics perspective based on phylogenetics,establishes various AD precision medical models,and uncovers potential mitochondria-related biomarkers and drug targets,suggesting novel strategies for the prevention and treatment of AD.The first chapter provides an overview of AD-related pathological mechanisms,AD mitochondria-related pathological mechanisms,and the application and challenges of multi-omics research in AD.The second chapter is based on genomic data,firstly,mitochondrial genome-wide association analysis and genome-wide epistasis analysis were used to uncover mitochondrial-nuclear interaction loci that are closely associated with AD risk.A total of14,340 interacting pairs were obtained in different control groups.Of these,1,650 genes corresponding to nuclear-associated loci and 1,474 nucleus genes with subcellular localization to mitochondria served as the two classes of mitochondria-associated genes for subsequent analysis in this study.Then,we evaluated the predictive validity of these mitochondrial-associated genes/loci for AD risk based on the Polygenic Risk Score(PRS)and characterized individual resistance/resilience to AD by incorporating mitochondrial information.Significantly improved model performance was demonstrated in both the ADNI dataset(N = 1,550)and the ROSMAP dataset(N = 2,090)with the addition of mitochondrial-associated loci,and the integration of some of the mitochondrial-associated loci with significant association loci based on Genome-Wide Association Study(GWAS),providing more accurate and stable models.We further explored and annotated important mitochondria-related loci and their biological functions in these models.The third chapter is based on transcriptomics data,we constructed co-expression modules closely associated with AD and mitochondria through co-expression networks,and mitochondrial-nuclear gene regulatory networks through gene dependency networks to explore more genes indirectly associated with mitochondria.In our study,the AD risk prediction model constructed based on 91 hub genes of the co-expression network achieved robust prediction results in multiple independent data sets and significantly outperformed the models constructed based on GWAS-identified risk genes and differential expression genes.The two modules with intensive dependencies found in this study based on the genedependency network were both associated with mitochondrial translation-related pathways,and the major members were Mitochondrial Ribosomal Protein(MRP)genes.The important role of MRPs in the mitochondrial machinery of AD was demonstrated.Moreover,by ranking the genetic importance of all samples,seven nutrients with promising preventive and ameliorative effects on AD were proposed.In addition,through transcriptome association analysis of multiple tissues,our study further uncovered mitochondria-related genes that are closely associated with AD risk and assessed their mutational effects.In the fourth chapter,mitochondria-related regulatory mechanisms in AD are explored at the methylation level based on epigenomic data.The differential analysis reveals that methylation levels may influence mitochondrial homeostasis by affecting c AMP signaling.In addition,our study identified two mitochondria-related functional methylation modules(NOS2 module and GABRG3 module)that are involved in biological functions among which calcium signaling pathway,neuroinflammatory and glutamatergic signaling and γ-aminobutyric acid signaling pathway have been confirmed to be related to mitochondria and AD by many studies.Our study suggested that genes in these modules may function together at the epigenetic level,increasing understanding of how mitochondria regulate neuronal homeostasis under methylation conditions.Targeting one or more genes in these modules may have a more pronounced therapeutic effect.Finally,through epigenomic association analysis,we further uncovered additional mitochondria-associated methylation loci that are closely associated with AD risk.It revealed that external factors such as vitamins and hormones may affect mitochondrial function by influencing gene methylation levels,which in turn leads to the development of psychiatric disorders.Finally,17mitochondria-associated methylation markers in peripheral blood were proposed by methylation prediction model.The fifth chapter of this paper provides a comprehensive and systematic exploration of AD mitochondrial pathogenesis based on multi-omics data.Six causal relationships are used,combining the results of expression volume trait loci(e QTL and m QTL)to construct a causal regulatory network of mitochondrial-nuclear genes;integrating chromatin interaction data(Hi-C),transcription factor binding sites and single-cell ATAC sequencing data to construct four neuronal cell-specific gene regulatory networks.The close regulatory relationship between mitochondria and microglia was revealed;the genomic,transcriptomic and epigenomic association results were integrated,and the biological modules of functions in different association data were identified.We suggested the potential major driver roles of mitochondria-located genes IFI6 and CMPK2.In addition,we used various popular multi-omics integration algorithms to construct an AD susceptible population classification model and an AD risk prediction model based on unsupervised and supervised approaches,respectively,to reveal important multi-omics markers associated with mitochondria.In summary,our study explored the key role of mitochondria in AD pathophysiology based on phylogenetics and multiple bioinformatic analyses,and constructed various AD precision medical models at multi-omics level.At the same time,based on genetic epistasis,the regulatory relationship of mitochondria-nuclear gene interactions in AD disease progression was analyzed.Our study provides new ideas to analyze the mitochondrial pathological mechanism of AD,which has implications for the early screening,prevention,precision medicine and drug development of AD.