Together with our in vivo data in several AD mouse models demonstrating higher brain levels of microglial and brain CH25H mRNA, we hypothesize that 25-HC may be an important pro-inflammatory chemical messenger whose production and secretion will greatly amplify cytokine secretion in apoE4-expressing microglia in a paracrine or autocrine manner (Supplementary Fig. 3), and may thus contribute either indirectly or even directly to the neuroinflammation and neurodegeneration that characterize AD. Here, APOE is linked to Alzheimer disease.