Decoding Pathogenic and Resilient Gene Regulatory Interactions in Alzheimer's Disease

The molecular basis of cognitive resilience in Alzheimers disease (AD), wherein individuals harbor substantial neuropathology yet maintain cognition, remains poorly understood. To systematically decode the regulatory logic underlying divergent cognitive outcomes, we constructed the largest cell-type-resolved gene regulatory network (GRN) atlas of AD to date, profiling 1.7 million nuclei from 687 individuals classified as Controls, cognitively Resilient, or AD dementia across 27 cell types in the human dorsolateral prefrontal cortex. From 223 high-confidence transcription factor regulons, we identify a three-state framework of transcriptional dysregulation: homeostatic erosion of IRF8/STAT1 interferon programs in microglia (State I), compensatory NF-{kappa}B suppression via BCL6 in glial populations that distinguishes resilient from demented individuals despite equivalent neuropathological burden (State II), and pathogenic escalation through FLI1/IKZF1 network expansion driving vascular-immune remodeling in AD (State III). NF-{kappa}B emerges as the central regulatory hub, with BCL6-mediated repression and FLI1/RELA-driven activation constituting opposing molecular switches that determine cognitive trajectory. These findings, replicated across independent cohorts, reframe resilience as an active regulatory state rather than attenuated disease, and nominate BCL6, IRF8, and FLI1 as priority targets for interventions aimed at extending the compensatory window before dementia onset.