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

INTRODUCTION: Cognitive resilience in Alzheimer's disease (AD), wherein individuals maintain cognition despite substantial neuropathology, implies protective regulatory programs that remain poorly characterized. METHODS: 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. RESULTS: Analysis 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.