biostudies-literatureLiu CCNIA NIH HHSNCI NIH HHS1020-1033https://www.ebi.ac.uk/biostudies/studies/S-EPMC10009873biostudies-literatureUnknown25(8)The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young miNature neurosciencePeripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.PMC10009873RF1 AG057181RF1 AG062110RF1 AG054014P30 CA016672R37 AG027924U19 AG069701U01 AG046170R21 AG057981U01 AG052411RF1 AG046205Doss SVKim BYSBu GRen YFu YKanekiyo TJia LAsmann YWMartens YAWang MBastea LWang NZhao NRosenberg CLKuchenbecker LAChen YRogers JQuicksall ZSWang XZhao JWang ZZhang BLiu CCLinares CYamazaki AKurti AKong DStorz PQiao WYamazaki YLi ZJeevaratnam STrottier ZAFryer JDShue FKnight JFelton LInoue YPeng JfalsePeripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mi2022-01-01T00:00:00Z2022 Aug2025-04-21T16:10:08.536Z2025-04-21T16:10:08.536ZS-EPMC100098733591518010.1038/s41593-022-01127-0