A novel microglial transcription profile is driven by sex and APOE4 interactions in both mouse and human models of Alzheimer’s disease

Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We then confirm these findings in human cells, using microglia derived from induced pluripotent stem cells. Bulk RNA-seq profiles of microglia sorted from mice carrying human APOE (introduced by targeted replacement) on control or 5xFAD genetic background and human microglia differentiated from induced pluripotent stem cells derived from healthy control patients genotyped for APOE +/- heavy metal treatment