Fig. 1

Apolipoprotein E4 (APOE4) increases Alzheimer’s disease risk and worsens pathology. However, the influence of peripheral ApoE isoforms on CNS function is still unclear. In their recent publication, Liu et al. leverage a novel mouse model expressing hepatic ApoE3 or ApoE4 on an Apoe knockout background to show that liver-derived E4, but not E3, has multiple pathogenic effects. Several of these effects, namely cognitive and cerebrovascular function, can be improved by treating aged mice with young E3 plasma, while E4 plasma exacerbates deficits. Additionally, young E3 plasma, or co-treatment with young E4 plasma plus Timp3, improved endothelial cell function in a human iPSC-derived endothelial cell system. This exciting study highlights the important interaction between peripheral ApoE and vascular-mediated AD pathogenesis, and raises several important additional questions for the field