{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:15:25Z","timestamp":1777396525051,"version":"3.51.4"},"reference-count":39,"publisher":"SAGE Publications","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) is the leading cause of dementia, with its prevalence increasing as the global population ages. AD is a multifactorial and intricate neurodegenerative disease with pathological changes varying from person to person. Because the mechanism of AD is highly controversial, effective treatments remain a distant prospect. Currently, one of the most promising hypotheses posits mitochondrial dysfunction as an early event in AD diagnosis and a potential therapeutic target. Objective: Here, we adopted a systems medicine strategy to explore the mitochondria-related mechanisms of AD. Then, its implications for discovering nutrients combatting the disease were demonstrated. Methods: We employed conditional mutual information (CMI) to construct AD gene dependency networks. Furthermore, the GeneRank algorithm was applied to prioritize the gene importance of AD patients and identify potential anti-AD nutrients targeting crucial genes. Results: The results suggested that two highly interconnected networks of mitochondrial ribosomal proteins (MRPs) play an important role in the regulation of AD pathology. The close association between mitochondrial ribosome dysfunction and AD was identified. Additionally, we proposed seven nutrients with potential preventive and ameliorative effects on AD, five of which have been supported by experimental reports. Conclusions: Our study explored the important regulatory role of MRP genes in AD, which has significant implications for AD prevention and treatment.<\/jats:p>","DOI":"10.3233\/jad-230366","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T13:42:29Z","timestamp":1694526149000},"page":"1709-1722","source":"Crossref","is-referenced-by-count":1,"title":["Dissecting Mitochondrial Mechanisms of Alzheimer\u2019s Disease Using Gene Dependency Network and Its Implications for Discovering Nutrients Combatting the Disease"],"prefix":"10.1177","volume":"95","author":[{"given":"Xuan","family":"Xu","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China"},{"name":"College of Life Sciences, Anhui Medical University, Hefei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing-Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Yu","family":"Meng","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China"},{"name":"Health Science Center, Hubei Minzu University, Enshi, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Xing","family":"Li","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-230366_ref1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S1474-4422(20)30440-3","article-title":"New insights into atypical Alzheimer\u2019s disease in the era of biomarkers","volume":"20","author":"Graff-Radford","year":"2021","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-230366_ref2","doi-asserted-by":"crossref","first-page":"113321","DOI":"10.1016\/j.expneurol.2020.113321","article-title":"Mitochondria in Alzheimer\u2019s disease and their potential role in Alzheimer\u2019s proteostasis","volume":"330","author":"Weidling","year":"2020","journal-title":"Exp Neurol"},{"key":"10.3233\/JAD-230366_ref3","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement"},{"key":"10.3233\/JAD-230366_ref4","doi-asserted-by":"crossref","first-page":"e12385","DOI":"10.1002\/trc2.12385","article-title":"Alzheimer\u2019s disease drug development pipeline: 2023","volume":"9","author":"Cummings","year":"2023","journal-title":"Alzheimers Dement (N Y)"},{"key":"10.3233\/JAD-230366_ref5","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S1474-4422(10)70119-8","article-title":"Alzheimer\u2019s disease: Clinical trials and drug development","volume":"9","author":"Mangialasche","year":"2010","journal-title":"Lancet Neurol"},{"key":"10.3233\/JAD-230366_ref6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3390\/nu11010085","article-title":"The role of nutrients in reducing the risk for noncommunicable diseases during aging","volume":"11","author":"Bruins","year":"2019","journal-title":"Nutrients"},{"key":"10.3233\/JAD-230366_ref7","doi-asserted-by":"crossref","first-page":"9874159","DOI":"10.1155\/2019\/9874159","article-title":"Nutrients in the prevention of Alzheimer\u2019s disease","volume":"2019","author":"Cremonini","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"10.3233\/JAD-230366_ref8","first-page":"109322","article-title":"Vitamin D receptor regulates transcription of mitochondrial DNA anddirectly interacts with mitochondrial DNA and TFAM","volume":"116","author":"Gezen-Ak","year":"2023","journal-title":"J NutrBiochem"},{"key":"10.3233\/JAD-230366_ref9","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1111\/bph.14585","article-title":"Mitochondrial dysfunction in Alzheimer\u2019s disease: Role in pathogenesis and novel therapeutic opportunities","volume":"176","author":"Perez Ortiz","year":"2019","journal-title":"Br J Pharmacol"},{"key":"10.3233\/JAD-230366_ref10","doi-asserted-by":"crossref","first-page":"4850","DOI":"10.3390\/ijms22094850","article-title":"Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer\u2019s disease","volume":"22","author":"Sharma","year":"2021","journal-title":"Int J Mol Sci"},{"key":"10.3233\/JAD-230366_ref11","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.3390\/biomedicines10081782","article-title":"Systems genetic identification of mitochondrion-associated Alzheimer\u2019s disease genes and implications for disease risk prediction","volume":"10","author":"Xu","year":"2022","journal-title":"Biomedicines"},{"key":"10.3233\/JAD-230366_ref12","doi-asserted-by":"crossref","first-page":"e40918","DOI":"10.1371\/journal.pone.0040918","article-title":"A model-based method for gene dependency measurement","volume":"7","author":"Zhang","year":"2012","journal-title":"PLoS One"},{"key":"10.3233\/JAD-230366_ref13","doi-asserted-by":"crossref","first-page":"e92023","DOI":"10.1371\/journal.pone.0092023","article-title":"Inferring gene dependency network specific to phenotypic alteration based on gene expression data and clinical information of breast cancer","volume":"9","author":"Zhou","year":"2014","journal-title":"PLoS One"},{"key":"10.3233\/JAD-230366_ref14","doi-asserted-by":"crossref","first-page":"3586","DOI":"10.3390\/cancers13143586","article-title":"Systems pharmacology-based precision therapy and drug combination discovery for breast cancer","volume":"13","author":"Cui","year":"2021","journal-title":"Cancers"},{"key":"10.3233\/JAD-230366_ref16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/1471-2105-6-233","article-title":"GeneRank: Using search engine technology for the analysis of microarray experiments","volume":"6","author":"Morrison","year":"2005","journal-title":"BMC Bioinformatics"},{"key":"10.3233\/JAD-230366_ref17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1212\/WNL.0b013e3181cb3e25","article-title":"Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI): Clinical characterization","volume":"74","author":"Petersen","year":"2010","journal-title":"Neurology"},{"key":"10.3233\/JAD-230366_ref18","doi-asserted-by":"crossref","first-page":"628","DOI":"10.2174\/156720512801322573","article-title":"Overview and findings from the religious orders study","volume":"9","author":"Bennett","year":"2012","journal-title":"Curr Alzheimer Res"},{"key":"10.3233\/JAD-230366_ref19","doi-asserted-by":"crossref","first-page":"646","DOI":"10.2174\/156720512801322663","article-title":"Overview and findings from the rush Memory and Aging Project","volume":"9","author":"Bennett","year":"2012","journal-title":"Curr Alzheimer Res"},{"key":"10.3233\/JAD-230366_ref20","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2013.03.030","article-title":"Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer\u2019s disease","volume":"153","author":"Zhang","year":"2013","journal-title":"Cell"},{"key":"10.3233\/JAD-230366_ref21","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"10.3233\/JAD-230366_ref22","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1109\/TPAMI.2005.159","article-title":"Feature selection based on mutual information: Criteria of max-dependency, max-relevance, and min-redundancy","volume":"27","author":"Peng","year":"2005","journal-title":"IEEE Trans Pattern Anal Mach Intell"},{"key":"10.3233\/JAD-230366_ref23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1471-2105-4-2","article-title":"An automated method for finding molecular complexes in large protein interaction networks","volume":"4","author":"Bader","year":"2003","journal-title":"BMC Bioinformatics"},{"key":"10.3233\/JAD-230366_ref24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/pro.3978","article-title":"The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions","volume":"30","author":"Oughtred","year":"2021","journal-title":"Protein Sci"},{"key":"10.3233\/JAD-230366_ref25","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nmeth.4077","article-title":"OmniPath: Guidelines and gateway for literature-curated signaling pathway resources","volume":"13","author":"T\u00fcrei","year":"2016","journal-title":"Nat Methods"},{"key":"10.3233\/JAD-230366_ref26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nmeth.4083","article-title":"A scored human protein-protein interaction network to catalyze genomic interpretation","volume":"14","author":"Li","year":"2017","journal-title":"Nat Methods"},{"key":"10.3233\/JAD-230366_ref27","doi-asserted-by":"crossref","first-page":"46398","DOI":"10.18632\/oncotarget.18189","article-title":"Identifying prognostic signature in ovarian cancer using DirGenerank","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"10.3233\/JAD-230366_ref28","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"10.3233\/JAD-230366_ref29","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s11481-013-9479-z","article-title":"The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system","volume":"9","author":"Funa","year":"2014","journal-title":"J Neuroimmune Pharmacol"},{"key":"10.3233\/JAD-230366_ref30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.mam.2018.01.006","article-title":"PDGF\/PDGFR axis in the neural systems","volume":"62","author":"Sil","year":"2018","journal-title":"Mol Aspects Med"},{"key":"10.3233\/JAD-230366_ref31","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.ejmech.2016.10.060","article-title":"A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer\u2019s disease","volume":"128","author":"Sameem","year":"2017","journal-title":"Eur J Med Chem"},{"key":"10.3233\/JAD-230366_ref32","doi-asserted-by":"crossref","first-page":"6017","DOI":"10.1007\/s12035-019-1479-4","article-title":"Upregulation of proteolytic pathways and altered protein biosynthesis underlie retinal pathology in a mouse model of Alzheimer\u2019s disease","volume":"56","author":"Mirzaei","year":"2019","journal-title":"Mol Neurobiol"},{"key":"10.3233\/JAD-230366_ref33","doi-asserted-by":"crossref","first-page":"110952","DOI":"10.1016\/j.exger.2020.110952","article-title":"The effects of environmental stressors on candidate aging associated genes","volume":"137","author":"Andrawus","year":"2020","journal-title":"Exp Gerontol"},{"key":"10.3233\/JAD-230366_ref34","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature12188","article-title":"Mitonuclear protein imbalance as a conserved longevity mechanism","volume":"497","author":"Houtkooper","year":"2013","journal-title":"Nature"},{"key":"10.3233\/JAD-230366_ref35","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/nm1653","article-title":"Classification and prediction of clinical Alzheimer\u2019s diagnosis based on plasma signaling proteins","volume":"13","author":"Ray","year":"2007","journal-title":"Nat Med"},{"key":"10.3233\/JAD-230366_ref36","doi-asserted-by":"crossref","first-page":"e29868","DOI":"10.1371\/journal.pone.0029868","article-title":"Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer\u2019s disease","volume":"7","author":"Bj\u00f6rkqvist","year":"2012","journal-title":"PLoS One"},{"key":"10.3233\/JAD-230366_ref37","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1042\/BJ20051364","article-title":"Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members","volume":"395","author":"Hermey","year":"2006","journal-title":"Biochem J"},{"key":"10.3233\/JAD-230366_ref38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41580-020-00313-x","article-title":"NAD+metabolism and its roles in cellular processes during ageing","volume":"22","author":"Covarrubias","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"10.3233\/JAD-230366_ref39","doi-asserted-by":"crossref","first-page":"668491","DOI":"10.3389\/fcell.2021.668491","article-title":"NAD+in Alzheimer\u2019s disease: Molecular mechanisms and systematic therapeutic evidence obtained in vivo","volume":"9","author":"Wang","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"10.3233\/JAD-230366_ref40","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3233\/JAD-181054","article-title":"Cognitive improvement with glutathione supplement in Alzheimer\u2019s disease: A way forward","volume":"68","author":"Mandal","year":"2019","journal-title":"J Alzheimers Dis"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-230366","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:08:30Z","timestamp":1777370910000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-230366"}},"subtitle":[],"editor":[{"given":"Jiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,10]]},"references-count":39,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.3233\/jad-230366","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,10]]}}}