Gene regulatory programs of cognitive resilience and pathogenesis in Alzheimer's disease.

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.

DISCUSSIONReplicated 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.