Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement.

Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains unclear. Here, we used an inducible APOE "switch" model to selectively replace microglial E4 with E2 in older adult mice while maintaining E4 expression in other CNS and peripheral cells. Following a Western diet, microglial E2 replacement was associated with fewer phago-lysosomal microglia and decreased apoE localization within these phago-lysosomal microglia. Following a peripheral inflammatory stimulus (LPS), microglial E2 replacement was linked with increased expression of metabolic and immune-related pathways. Together, these findings indicate that microglial E2 expression is associated with selective cellular and transcriptional changes while E4 continues to be expressed by other cell types.