The adaptor protein DAB2 cell-autonomously links APOE with disease-associated microglia (DAM)/TREM2 state dysregulation associated with Alzheimer's disease

The neuron-secreted Reelin (RELN) protein and its adaptor DAB1 modify Alzheimer's disease (AD) risk through genetic interaction with APOE4. While RELN and APOE4 exert antagonistic effects on amyloid and Tau pathology in mice, how risk is conferred in the human brain remains unclear. The related adaptor DAB2 endocytoses RELN/APOE receptors and, via LRP8, modulates non-canonical pro-inflammatory signalling in non-neuronal cells. We hypothesised that RELN and APOE signalling directly influence microglial function to modify AD risk. Integrating human brain transcriptomics, a Reln-deficient mouse, and DAB1/DAB2 knock-down in APOE isogenic iPSC-microglia, we found that microglial DAB1/DAB2 pathways were dynamically regulated across the lifespan, with DAB2 dysregulated with increasing amyloid pathology. DAB2 transcriptional networks correlated with disease- and lipid- associated microglial states (DAM/LDAM) linked to networks expressing dementia-risk loci (TREM2, GRN, ACE, SORL1) and associated with endolysosomal and lipid-handling pathways. DAB2- knockdown cell-autonomously shifted microglia away from gene networks enriched in DAM/TREM2 states and towards pro-inflammatory cytokine-responsive states and TNFNF{kappa}B pathways. APOE4/E4 microglia showed elevated APOE and reduced DAB1pY232 under inflammatory stress, and blunted DAB2-knockdown transcriptomic responses, consistent with pathway-level genetic interaction. In vivo, RELN-deficiency reduced microglial ramification and increased CD68. These findings identify DAB2 as a regulator of microglial state transitions and a modifier of dementia-risk networks linking APOE genotype to inflammatory, phagocytic and amyloid-beta clearance pathways relevant to AD.