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Recent studies have revealed incontrovertible roles of astrocytes in the pathology of AD. Considering the conflicting behaviours of astrocytes in AD brain, they have been proposed to have subtypes. In this study, astrocytes from two publicly available single-nuclei transcriptome datasets were integrated to provide in-depth characterization of astrocyte subtypes in AD. Differentially expressed genes within each astrocyte subtype were analyzed by mapping them onto a human protein\u2013protein interaction network to discover subnetworks with biologically relevant genes. Integrating single-nuclei datasets and using network-based analysis approach led to higher sensitivity in capturing AD-related genes compared to traditional approaches. One of the identified subtypes was highly representative of neurotoxic reactive astrocytes in AD. The results show that A1 reactive astrocytes could have an enhancing role for the amyloid beta and neurofibrillary tangle accumulation through MAPK10, MAPT, and TMED10, which were all found to be differentially expressed in this subtype during AD in our analysis. Moreover, single-nuclei ATAC-Seq data from the same tissue was re-analyzed to evaluate astrocyte subtypes at multi-omic level. It was found that astrocyte subtypes underwent epigenetic reprogramming during AD. Potential transcription factors were also identified for the regulation of the genes that exhibited alterations in both promoter accessibility and gene expression in AD. Comparative analysis of single-nuclei RNA-Seq and ATAC-Seq datasets showed that PTN gene, which was reported to be important for AD pathology, is likely regulated by ATF3 transcription factor in subtype-specific manner in astrocytes.<\/jats:p>","DOI":"10.1007\/s12035-025-04965-8","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T17:58:49Z","timestamp":1745949529000},"page":"11611-11631","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Functional Specificity of Astrocyte Subtypes in Alzheimer\u2019s Disease: Decoding Disease Mechanisms Through Network-based Analysis of Integrated Single-Nuclei Multi-Omic Data"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-1055","authenticated-orcid":false,"given":"At\u0131lay","family":"\u0130lg\u00fcn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8262-4420","authenticated-orcid":false,"given":"Tunahan","family":"\u00c7ak\u0131r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"4965_CR1","doi-asserted-by":"publisher","first-page":"a006189","DOI":"10.1101\/cshperspect.a006189","volume":"1","author":"A Serrano-Pozo","year":"2011","unstructured":"Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. 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