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We developed a framework linking cell\u2010type\u2013specific polygenic risk profiles to precision medicine in AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Cell\u2010based polygenic risk scores (cbPRSs) derived from single\u2010nucleus RNA\u2010seq co\u2010expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph\u2010based PageRank algorithm and candidate drugs were validated in human\u2010induced pluripotent stem cell (hiPSC)\u2013derived astrocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Cell\u2010based PRS analysis identified two genetic risk axes independent of network cell\u2010type labels: an apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      )\u2013concentrated axis (Ast\u2010M2\/Oli\u2010M45) and an\n                      <jats:italic>APOE<\/jats:italic>\n                      \u2010independent axis (Ast\u2010M10\/Oli\u2010M50), which predicted accelerated progression to AD (hazard ratio: 1.25\u20132.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High\u2010risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the\n                      <jats:italic>APOE<\/jats:italic>\n                      \u2010containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced\n                      <jats:italic>APOE<\/jats:italic>\n                      and complement\n                      <jats:italic>C4<\/jats:italic>\n                      gene expression in hiPSC\u2010derived astrocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>By integrating cell\u2010based genetic risk with network\u2010level target prioritization, this framework enables robust patient stratification and experimental target validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71895","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:40:26Z","timestamp":1791294026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell\u2010based polygenic 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