ApoE4, with an allele frequency of 14% in these populations, is linked to an increased risk of developing sporadic AD as well as a decreased age of onset compared to inherited apoE3.Recent studies suggest that there seem to be close interrelationships between abnormal protein accumulation or degradation, oxidative stress and mitochondrial dysfunction.The aim of this study was to investigate the role ofApoE isoform, mitochondria and oxidative stress in disease progression in AD mouse model.In Y-maze and new object recognition test, ApoEε4/4 mouse showed worse learning and memory abilities.In vitro analysis of immunofluorescence confocal microscopy seemed to reveal that ApoE 4 localizes with the mitochondria from primary cultured astrocytes.Western blot analyses also showed that the amount of COXIV and SOD2 in ApoEε4/4 mouse is lower than in ApoEε3/3 mouse.Mitochondrial dysfunction is further proved by quantitative proteomics based on label-free.With the measure of GPX4 mRNA and 2 markers of oxidative stress (GSH/GSSG and MDA) in cortex and hippocampus, the level of oxidative stress in ApoEε4/4 mouse is obviously higher than in ApoEε3/3 mouse.After adding cholesterol, the GPX4 and GPX1 mRNA levels were significantly increased in C6 Stable-transfect ApoEε4/4 cell line while they were not changed in ApoEε3/3 group.Our existing data give a hint that ApoE 4 could affect the normal function of mitochondria and further lead to the leak of ROS with aging.