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Among the molecular players involved, the transcription factors (TFs) can regulate the expression of AD-related peptides (\u03b2\u2010amyloid and tau). We aim to unveil reconstructed TF-centered networks and their dynamics across multiple brain regions. In this study, we conducted an exhaustive differential gene expression analysis, reconstructed TF-TF-centered regulatory networks, and performed master-regulation analyses across multiple regions. We used bulk RNA-seq data from 2,229 post-mortem samples from the ROSMAP, MAYO, and MSBB cohorts. To place these regulatory programs in a disease-relevant context, we integrated protein\u2013protein interaction (PPI) data, experimental TF-target data, and AD-associated genetic risk loci as a translational layer. We assessed TF-centered regulons for 1,605 TFs and identified 354 master-regulators (MR-TFs) across multiple brain regions, including the parahippocampal gyrus, temporal cortex, and cerebellum, which exhibited the highest numbers of regulons. Overall, regulons fell within a moderate size range (median 55 targets), rather than into extensive large networks. Novel MR-TFs, including\n                    <jats:italic>ADCYAP1, TEAD2, BCL6, MAFF, NFKBIA,<\/jats:italic>\n                    were consistently identified as MR-TFs across tissues in AD. Furthermore,\n                    <jats:italic>GUCY1B1<\/jats:italic>\n                    ,\n                    <jats:italic>RBFOX2<\/jats:italic>\n                    , and\n                    <jats:italic>MEF2C<\/jats:italic>\n                    were found conserved in the parahippocampal gyrus, inferior frontal gyrus, and posterior cingulate cortex\n                    <jats:italic>.<\/jats:italic>\n                    Additionally, our work identified the well-known AD-related genes\n                    <jats:italic>BIN1<\/jats:italic>\n                    ,\n                    <jats:italic>EGFR<\/jats:italic>\n                    , and\n                    <jats:italic>SPI1<\/jats:italic>\n                    as MR-TFs, reinforcing their functional roles as susceptibility risk markers in AD. This work established an MR-TF-centered integrated regulatory network map of AD, revealing MR-TFs as factors that orchestrate gene deregulation in a region- and cell-context\u2013dependent approach, and providing a robust foundation for mechanistic and translational investigations in neurodegeneration.\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-05745-8","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:26:05Z","timestamp":1771835165000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulon Reconstruction Uncovers Novel Deregulated Factors in Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"63","author":[{"given":"Marcella Vit\u00f3ria","family":"Bel\u00e9m-Souza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Barra-Matos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilderlanio Santana","family":"de Ara\u00fajo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"5745_CR1","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","volume":"54","author":"C Bellenguez","year":"2022","unstructured":"Bellenguez C, K\u00fc\u00e7\u00fckali F, Jansen IE et al (2022) New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias. 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