{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T08:24:50Z","timestamp":1794299090128,"version":"4.9.0"},"reference-count":46,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuroinflammation, particularly involving reactive astrocytes, plays a pivotal role in Alzheimer's disease (AD) progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>However, the causal genes and regulatory pathways linking astrocyte reactivity to AD risk remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a multi-omics summary-data-based Mendelian randomization (SMR) analysis, integrating large-scale AD GWAS data with methylation (mQTLs), expression (eQTLs), and protein (pQTLs) data for 514 reactive astrocyte-related genes. Causal inference was strengthened using colocalization and tissue-specific validation, and pathway enrichment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our multi-omics SMR analysis identified a core set of high-confidence genes related to reactive astrocytes with putatively causal roles in AD. Based on mQTL-eQTL analysis,\n                      <jats:italic toggle=\"yes\">SPARC<\/jats:italic>\n                      (cg08331313),\n                      <jats:italic toggle=\"yes\">RPS6KA2<\/jats:italic>\n                      (12 CpG sites), and\n                      <jats:italic toggle=\"yes\">LEP<\/jats:italic>\n                      (4 CpG sites) demonstrated significant regulatory cascades, where methylation changes modulated gene expression and subsequently influenced AD risk. The eQTL-pQTL analysis revealed GCDH as genes with strong expression-protein correlations. Cross-tissue validation between blood and brain pinpointed a robust set of seven genes, including\n                      <jats:italic toggle=\"yes\">MAPK3<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">HLA-DQB1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">CSF3<\/jats:italic>\n                      , that consistently associate with AD risk, highlighting systemic effects. Functional and network analyses of these causal candidates revealed that they converge upon the\n                      <jats:italic toggle=\"yes\">MAPK<\/jats:italic>\n                      signaling pathway as a central mechanistic hub in both peripheral blood and brain tissue. Furthermore, network analysis identified seven hub genes, including\n                      <jats:italic toggle=\"yes\">MAPK3<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">LEP<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">STAT1<\/jats:italic>\n                      , as critical regulators within this astrocyte-centered AD network.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study systematically identifies genetically predicted reactive astrocyte-related genes in AD pathogenesis through multi-omics Mendelian randomization, highlighting MAPK signaling as a putatively causal mechanistic hub.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261489741","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:11:16Z","timestamp":1790165476000},"page":"749-764","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A multi-omics Mendelian randomization study identifies putatively causal genes and pathways for Alzheimer's disease associated with reactive astrocytes"],"prefix":"10.1177","volume":"114","author":[{"given":"Qi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Naval Medical University (Shanghai Changzheng Hospital), Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8583-9046","authenticated-orcid":false,"given":"Xu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.4c00339"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100094"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1347987"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11111598"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13678"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom14101204"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2024.1515981"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03111-7"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2024.02.008"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa119"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104432"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.01021"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202950"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102947"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal4230"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00913-z"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj1541"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06592-6"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00978-w"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac376"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","unstructured":"Vigorito E Lin W-Y Starr C et al. 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