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

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Cognitive resilience in Alzheimer's disease (AD) is poorly understood.
• Individuals with AD pathology can maintain cognition, suggesting underlying regulatory mechanisms.
• A cell-type-resolved gene regulatory network (GRN) atlas is needed to decode these mechanisms.

Purpose of the Study:

• To construct the largest cell-type-resolved GRN atlas of AD.
• To identify regulatory logic distinguishing resilient individuals from those with AD dementia.
• To uncover molecular switches governing cognitive trajectory in AD.

Main Methods:

• Profiling 1.7 million nuclei from 687 individuals (Controls, Resilient, AD dementia).
• Analysis across 27 cell types in the human dorsolateral prefrontal cortex.
• Identification of 223 transcription factor regulons and a three-state framework of transcriptional dysregulation.

Main Results:

• Identified three states of transcriptional dysregulation: interferon program erosion (microglia), compensatory NF-κB suppression (glial), and pathogenic vascular-immune remodeling (AD).
• NF-κB is a central regulatory hub, with BCL6 and FLI1/RELA acting as opposing molecular switches.
• Findings were replicated across independent cohorts, reframing resilience as an active regulatory state.

Conclusions:

• Cognitive resilience in AD is an active regulatory state, not merely attenuated disease.
• BCL6, IRF8, and FLI1 are key regulators and potential therapeutic targets.
• Interventions targeting these factors may extend the compensatory window before dementia onset.