{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:51:49Z","timestamp":1788947509717,"version":"build-2803163510"},"posted":{"date-parts":[[2026,2,26]]},"group-title":"Genetic and Genomic Medicine","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>Cognitive resilience in Alzheimer\u2019s disease (AD), wherein individuals maintain cognition despite substantial neuropathology, implies protective regulatory programs that remain poorly characterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We constructed a cell-type-resolved gene regulatory network atlas from 1.7 million nuclei across 687 individuals spanning 26 cell types in the dorsolateral prefrontal cortex, classified as Control, Resilient, or AD dementia.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Analysis of 223 transcription factor regulons reveals a three-state regulatory framework: homeostatic erosion of IRF8\/STAT1 interferon programs (State I), compensatory NF-\u03baB suppression via BCL6 that distinguishes resilient from demented individuals (State II), and pathogenic FLI1\/IKZF1 network expansion driving vascular-immune remodeling (State III). NF-\u03baB emerges as the central hub, with BCL6-mediated repression and FLI1\/RELA-driven activation constituting opposing molecular switches.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>Replicated across independent cohorts, these findings model resilience as an active regulatory state and nominate stage-specific therapeutic strategies: restoring homeostatic programs, prolonging compensatory suppression, and constraining inflammatory escalation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.19.26346666","type":"posted-content","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T16:35:24Z","timestamp":1772123724000},"source":"Crossref","is-referenced-by-count":1,"title":["Gene regulatory programs of cognitive resilience and pathogenesis in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9611-9895","authenticated-orcid":false,"given":"Collin","family":"Spencer","sequence":"first","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.M.","family":"Prashant","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"PsychAD Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Bendl","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel E.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Fullard","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos","family":"Roussos","sequence":"additional","affiliation":[{"name":"Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051508201123000_2026.02.19.26346666v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(84)80190-4"},{"key":"2026051508201123000_2026.02.19.26346666v2.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1566067"},{"key":"2026051508201123000_2026.02.19.26346666v2.3","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2026051508201123000_2026.02.19.26346666v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.039"},{"key":"2026051508201123000_2026.02.19.26346666v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07606-7"},{"key":"2026051508201123000_2026.02.19.26346666v2.6","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00719-7"},{"key":"2026051508201123000_2026.02.19.26346666v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.02.005"},{"key":"2026051508201123000_2026.02.19.26346666v2.8","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012499"},{"key":"2026051508201123000_2026.02.19.26346666v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"2026051508201123000_2026.02.19.26346666v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0358-2"},{"key":"2026051508201123000_2026.02.19.26346666v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2026051508201123000_2026.02.19.26346666v2.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"2026051508201123000_2026.02.19.26346666v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.037"},{"key":"2026051508201123000_2026.02.19.26346666v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01774-5"},{"key":"2026051508201123000_2026.02.19.26346666v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07871-6"},{"key":"2026051508201123000_2026.02.19.26346666v2.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120352"},{"key":"2026051508201123000_2026.02.19.26346666v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.01.002"},{"key":"2026051508201123000_2026.02.19.26346666v2.18","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000219668.47116.e6"},{"key":"2026051508201123000_2026.02.19.26346666v2.19","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.59.2.198"},{"key":"2026051508201123000_2026.02.19.26346666v2.20","doi-asserted-by":"publisher","DOI":"10.1159\/000096129"},{"key":"2026051508201123000_2026.02.19.26346666v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-025-04687-5"},{"key":"2026051508201123000_2026.02.19.26346666v2.22","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.41.4.479"},{"key":"2026051508201123000_2026.02.19.26346666v2.23","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.43.11.2412"},{"key":"2026051508201123000_2026.02.19.26346666v2.24","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.46.6.1746"},{"key":"2026051508201123000_2026.02.19.26346666v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"2026051508201123000_2026.02.19.26346666v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0336-2"},{"key":"2026051508201123000_2026.02.19.26346666v2.27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa687"},{"key":"2026051508201123000_2026.02.19.26346666v2.28","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.17.533005"},{"key":"2026051508201123000_2026.02.19.26346666v2.29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac757"},{"key":"2026051508201123000_2026.02.19.26346666v2.30","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad031"},{"key":"2026051508201123000_2026.02.19.26346666v2.31","doi-asserted-by":"publisher","DOI":"10.1101\/2024.10.31.24316513"},{"key":"2026051508201123000_2026.02.19.26346666v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3318"},{"key":"2026051508201123000_2026.02.19.26346666v2.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2026051508201123000_2026.02.19.26346666v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.03.013"},{"key":"2026051508201123000_2026.02.19.26346666v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.009"},{"key":"2026051508201123000_2026.02.19.26346666v2.36","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1998010"},{"key":"2026051508201123000_2026.02.19.26346666v2.37","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-210026"},{"key":"2026051508201123000_2026.02.19.26346666v2.38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.741839"},{"key":"2026051508201123000_2026.02.19.26346666v2.39","doi-asserted-by":"publisher","DOI":"10.1038\/srep42054"},{"key":"2026051508201123000_2026.02.19.26346666v2.40","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.590480"},{"key":"2026051508201123000_2026.02.19.26346666v2.41","doi-asserted-by":"publisher","DOI":"10.1101\/2023.10.25.23297558"},{"key":"2026051508201123000_2026.02.19.26346666v2.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2008.07.048"},{"key":"2026051508201123000_2026.02.19.26346666v2.43","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05546-4"},{"key":"2026051508201123000_2026.02.19.26346666v2.44","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10654"},{"key":"2026051508201123000_2026.02.19.26346666v2.45","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00678-5"},{"key":"2026051508201123000_2026.02.19.26346666v2.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0695-9"},{"key":"2026051508201123000_2026.02.19.26346666v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0466-2"},{"key":"2026051508201123000_2026.02.19.26346666v2.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.009"},{"key":"2026051508201123000_2026.02.19.26346666v2.49","doi-asserted-by":"publisher","DOI":"10.1038\/nri3581"},{"key":"2026051508201123000_2026.02.19.26346666v2.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01315-6"},{"key":"2026051508201123000_2026.02.19.26346666v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.06.027"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.02.19.26346666","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:20:18Z","timestamp":1778858418000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.02.19.26346666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":51,"URL":"https:\/\/doi.org\/10.64898\/2026.02.19.26346666","relation":{},"subject":[],"published":{"date-parts":[[2026,2,26]]},"subtype":"preprint"}}