Apoe4 impairs microglia response to neurodegeneration in alzheimer’s disease

APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). We previously identified that APOE signaling governs the transcriptional regulation from homeostatic to neurodegenerative microglia (MGnD). However, the underlying mechanism for APOE4-mediated microglial dysregulation and its contribution to increased risk for developing AD, is unknown. Here we aimed to dissect the impact of microglial APOE4 on AD pathology, using CX3CR1-CREERT2 mice crossed to APOE-KI(E3 and E4)fl/fl:APP/PS1.We identified reduced numbers of MGnD per plaque in APP/PS1:APOE4-KI mice, despite their increased plaque load. Here we show that conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD-microglia in response to acute neurodegeneration and in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD-microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology and increased astrocytic recruitment towards plaques. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers. Our findings show that APOE4 is a negative regulator of MGnD-microglia in AD, and that its genetic deletion restores the induction of MGnD signature associated with reduction in plaque pathology. Taken together, these findings identify a cell-intrinsic role of APOE4 in the induction of dysfunctional MGnD microglia and their impaired response to neurodegeneration, which may provide new molecular targets to modulate and restore functional microglia in AD.