{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T04:21:07Z","timestamp":1770956467007,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T00:00:00Z","timestamp":1715385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD), a multifactorial neurodegenerative disorder, is prevalent among the elderly population. It is a complex trait with mutations in multiple genes. Although the US Food and Drug Administration (FDA) has approved a few drugs for AD treatment, a definitive cure remains elusive. Research efforts persist in seeking improved treatment options for AD. Here, a hybrid pipeline is proposed to apply text mining to identify comorbid diseases for AD and an omics approach to identify the common genes between AD and five comorbid diseases\u2014dementia, type 2 diabetes, hypertension, Parkinson\u2019s disease, and Down syndrome. We further identified the pathways and drugs for common genes. The rationale behind this approach is rooted in the fact that elderly individuals often receive multiple medications for various comorbid diseases, and an insight into the genes that are common to comorbid diseases may enhance treatment strategies. We identified seven common genes\u2014PSEN1, PSEN2, MAPT, APP, APOE, NOTCH, and HFE\u2014for AD and five comorbid diseases. We investigated the drugs interacting with these common genes using LINCS gene\u2013drug perturbation. Our analysis unveiled several promising candidates, including MG-132 and Masitinib, which exhibit potential efficacy for both AD and its comorbid diseases. The pipeline can be extended to other diseases.<\/jats:p>","DOI":"10.3390\/genes15050614","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:59:37Z","timestamp":1715677177000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comorbidity-Guided Text Mining and Omics Pipeline to Identify Candidate Genes and Drugs for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Iyappan Ramalakshmi","family":"Oviya","sequence":"first","affiliation":[{"name":"Department of Computer Science and Engineering, Amrita School of Computing, Amrita Vishwa Vidyapeetham, Chennai 641112, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Divya","family":"Sankar","sequence":"additional","affiliation":[{"name":"Department of Sciences, Amrita School of Engineering, Amrita Vishwa Vidyapeetham, Chennai 601103, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-3526","authenticated-orcid":false,"given":"Sharanya","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Stella Maris College, Chennai 600086, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6426-4548","authenticated-orcid":false,"given":"Archana","family":"Prabahar","sequence":"additional","affiliation":[{"name":"Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences (BGES), Cleveland State University, Cleveland, OH 44115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3156-4197","authenticated-orcid":false,"given":"Kalpana","family":"Raja","sequence":"additional","affiliation":[{"name":"School of Biomedical Informatics, University of Texas Health Science Center, Houston, TX 77030, USA"},{"name":"Section for Biomedical Informatics and Data Science, School of Medicine, Yale University, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New Insights into the Genetic Etiology of Alzheimer\u2019s Disease and Related Dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ridge, P.G., Mukherjee, S., Crane, P.K., and Kauwe, J.S.K. (2013). Alzheimer\u2019s Disease: Analyzing the Missing Heritability. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079771"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/978-1-0716-2305-3_15","article-title":"Extracting Significant Comorbid Diseases from MeSH Index of PubMed","volume":"2496","author":"Anand","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1002\/clc.23687","article-title":"Natural language processing for the assessment of cardiovascular disease comorbidities: The cardio-Canary comorbidity project","volume":"44","author":"Berman","year":"2021","journal-title":"Clin. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111223","DOI":"10.1016\/j.exger.2020.111223","article-title":"Motor signs in Alzheimer\u2019s disease and vascular dementia: Detection through natural language processing, comorbid features and relationship to adverse outcomes","volume":"146","author":"Iqbal","year":"2021","journal-title":"Exp. Gerontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/978-1-0716-2305-3_2","article-title":"Text Mining Protocol to Retrieve Significant Drug\u2013Gene Interactions from PubMed Abstracts","volume":"2496","author":"Anand","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.14694\/EdBook_AM.2012.32.156","article-title":"Application of Genomic and Proteomic Technologies in Biomarker Discovery","volume":"32","author":"Fertig","year":"2012","journal-title":"Am. Soc. Clin. Oncol. Educ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-biodatasci-072018-021211","article-title":"Connectivity Mapping: Methods and Applications","volume":"2","author":"Keenan","year":"2019","journal-title":"Annu. Rev. Biomed. Data Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/978-1-0716-2305-3_11","article-title":"A Hybrid Protocol for Identifying Comorbidity-Based Potential Drugs for COVID-19 Using Biomedical Literature Mining, Network Analysis, and Deep Learning","volume":"2496","author":"Prabahar","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/MCO.0000000000000159","article-title":"Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy","volume":"18","author":"Adams","year":"2015","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D1067","DOI":"10.1093\/nar\/gkr968","article-title":"GeneWeaver: A web-based system for integrative functional genomics","volume":"40","author":"Baker","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"W697","DOI":"10.1093\/nar\/gkac328","article-title":"SigCom LINCS: Data and metadata search engine for a million gene expression signatures","volume":"50","author":"Evangelista","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"246210","DOI":"10.6064\/2012\/246210","article-title":"The Genetics of Alzheimer\u2019s Disease","volume":"2012","author":"Barber","year":"2012","journal-title":"Scientifica"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cacabelos, R. (2020). Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093059"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13024-021-00452-5","article-title":"Protective genes and pathways in Alzheimer\u2019s disease: Moving towards precision interventions","volume":"16","author":"Seto","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/j.parkreldis.2015.10.010","article-title":"Association of type 2 diabetes GWAS loci and the risk of Parkinson\u2019s and Alzheimer\u2019s diseases","volume":"21","author":"Chung","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.mito.2018.04.004","article-title":"Etiology of type 2 diabetes and Alzheimer\u2019s disease: Exploring the mitochondria","volume":"43","author":"Silzer","year":"2018","journal-title":"Mitochondrion"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neulet.2018.03.036","article-title":"Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease","volume":"674","author":"Chung","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.trci.2019.08.005","article-title":"Alzheimer\u2019s disease pathology explains association between dementia with Lewy bodies and APOE-\u03b54\/TOMM40 long poly-T repeat allele variants","volume":"5","author":"Prokopenko","year":"2019","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s00401-020-02200-3","article-title":"APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer\u2019s disease","volume":"140","author":"Nguyen","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e25585","DOI":"10.1097\/MD.0000000000025585","article-title":"SORL1 mutations are associated with parkinsonian and psychiatric features in Alzheimer disease","volume":"100","author":"Qiu","year":"2021","journal-title":"Medicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.3233\/JAD-215067","article-title":"Association between Common Variants of APOE, ABCA7, A2M, BACE1, and Cerebrospinal Fluid Biomarkers in Alzheimer\u2019s Disease: Data from the PUMCH Dementia Cohort","volume":"85","author":"Dong","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.devcel.2015.01.022","article-title":"Cellular Functions of the Amyloid Precursor Protein from Development to Dementia","volume":"32","author":"Goldstein","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"142.e9","DOI":"10.1016\/j.neurobiolaging.2020.01.013","article-title":"Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer\u2019s disease in large cohort","volume":"89","author":"Vance","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_30","first-page":"165","article-title":"HFE gene variants, iron, and lipids: A novel connection in Alzheimer\u00e2\u20acTMs disease","volume":"5","author":"Schengrund","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S1474-4422(22)00437-9","article-title":"Lessons from Down syndrome and autosomal dominant Alzheimer\u2019s disease","volume":"22","author":"Fortea","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2212910","DOI":"10.1001\/jamanetworkopen.2022.12910","article-title":"Association of Alzheimer Disease with Life Expectancy in People with Down Syndrome","volume":"5","author":"Iulita","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1080\/15548627.2019.1633862","article-title":"MAPT\/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: A vicious cycle in Alzheimer neurodegeneration","volume":"16","author":"Feng","year":"2020","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S1474-4422(16)00127-7","article-title":"Genetic variations underlying Alzheimer\u2019s disease: Evidence from genome-wide association studies and beyond","volume":"15","author":"Cuyvers","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/19083","article-title":"A presenilin-1-dependent \u03b3-secretase-like protease mediates release of Notch intracellular domain","volume":"398","author":"Annaert","year":"1999","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.semcdb.2020.12.011","article-title":"Role of Notch signaling in neurovascular aging and Alzheimer\u2019s disease","volume":"116","author":"Kapoor","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1161\/CIRCRESAHA.118.314496","article-title":"Endothelial Notch1 in Pulmonary Hypertension","volume":"124","author":"Babicheva","year":"2019","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"299.e1","DOI":"10.1016\/j.neurobiolaging.2020.11.005","article-title":"Mutation analysis of TMEM family members for early-onset Parkinson\u2019s disease in Chinese population","volume":"101","author":"Li","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3233\/ADR-200177","article-title":"Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer\u2019s Disease","volume":"4","author":"Barthelson","year":"2020","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1097\/01.LAB.0000056995.07053.C0","article-title":"Nitric Oxide Synthase-3 Overexpression Causes Apoptosis and Impairs Neuronal Mitochondrial Function: Relevance to Alzheimer\u2019s-Type Neurodegeneration","volume":"83","author":"Chiche","year":"2003","journal-title":"Lab. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0304-3940(01)01694-9","article-title":"Nitric oxide synthase gene polymorphisms in Alzheimer\u2019s disease and dementia with Lewy bodies","volume":"303","author":"Singleton","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1065117","DOI":"10.3389\/fnagi.2022.1065117","article-title":"A combination of midlife diabetes mellitus and the apolipoprotein E \u03b54 allele increase risk for cognitive decline","volume":"14","author":"Lee","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1127481","DOI":"10.3389\/fendo.2023.1127481","article-title":"Is type 2 diabetes associated dementia a microvascular early-Alzheimer\u2019s phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?","volume":"14","author":"Takechi","year":"2023","journal-title":"Front. Endocrinol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/614\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:40:54Z","timestamp":1760107254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,11]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["genes15050614"],"URL":"https:\/\/doi.org\/10.3390\/genes15050614","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,11]]}}}