ArticlemedRxiv : the preprint server for health sciences2026
Gene regulatory programs of cognitive resilience and pathogenesis in Alzheimer's disease.
Collin Spencer, Prashant N M, PsychAD Consortium, Jaroslav Bendl, Gabriel E Hoffman, John F Fullard, Donghoon Lee, Panos Roussos
Abstract readPreprint
In one paragraphArticle in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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2 · The registryThe trial behind it
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3 · Its place in the literatureWho cites it
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4 · The recordCorrections and comments
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5 · Who and what moneyAuthors and funding
8 authors.
Collin SpencerCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-9611-9895 Prashant N MCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PsychAD Consortium
Jaroslav BendlCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Gabriel E HoffmanCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
John F FullardCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Donghoon LeeCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Panos RoussosCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Funding
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MProcurement and Characterization of Postmortem Brain TissueZICMH002903 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI MARENCO, STEFANO · 2009 to 2025
$56.0MSUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1MEPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3MRush Alzheimer's Disease Research CenterP30AG072975 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI Lisa L Barnes, Julie A. Schneider · 2021 to 2026
$24.7MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MMulti-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7MPathway discovery, validation and compound identification for Alzheimer's disease - SupplementU01AG046152 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2013 to 2017
$13.6MUnderstanding the molecular mechanisms that contribute to neuropsychiatric symptoms in Alzheimer DiseaseR01AG067025 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI FINKBEINER, STEVEN M, HAROUTUNIAN, VAHRAM · 2019 to 2023
$11.8MTO ADMINISTRATIVELY DE-OBLIGATE UNEXPENDED AND EXPIRING FISCAL YEAR 2020 FUNDING IN ACCORDANCE WITH 31 U.S.C. SECTION 1552 (A), IN PREPARATION FOR SEPTEMBER 30, 2025, CLOSING OF THE PERIOD OF AVAILABI75N95019C00049 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI HAROUTUNIAN, VAHRAM · 2019 to 2025
$11.8MAlzheimer variants: Propagation of shared functional changes across cellular networksU01AG072572 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI DE JAGER, PHILIP L, ST GEORGE-HYSLOP, PETER HENRY · 2021 to 2025
$8.5MDiscovery of Novel Proteomic Targets in Alzheimer's DiseaseU01AG046161 · NIA · EMORY UNIVERSITY · PI BENNETT, DAVID ALAN, GESCHWIND, DANIEL H · 2014 to 2018
$8.4MIntramural NIH HHS ZIC MH002903NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG072975NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG036042NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG048015NIA NIH HHS R01 AG066831NIA NIH HHS R01 AG067025NIA NIH HHS RC2 AG036547NIA NIH HHS RF1 AG057473NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG046161NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG072572NIH HHS 75N95019C00049
6 · The paper itselfAbstract
introductionCognitive resilience in Alzheimer's disease (AD), wherein individuals maintain cognition despite substantial neuropathology, implies protective regulatory programs that remain poorly characterized.
methodsWe 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.
resultsAnalysis of 223 transcription factor regulons reveals a three-state regulatory framework: homeostatic erosion of IRF8/STAT1 interferon programs (State I), compensatory NF-κB suppression via BCL6 that distinguishes resilient from demented individuals (State II), and pathogenic FLI1/IKZF1 network expansion driving vascular-immune remodeling (State III). NF-κB emerges as the central hub, with BCL6-mediated repression and FLI1/RELA-driven activation constituting opposing molecular switches. DISCUSSION: 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.
Indexed as
Alzheimer’s diseaseBCL6cognitive resiliencedorsolateral prefrontal cortexFLI1gene regulatory networksIKZF1IRF8microglianetwork rewiringNF-κBsingle-nucleus RNA-seqtranscription factors
Identifiers
PMID42051575
PMCPMC13119351
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