Sex difference in the association of APOE4 with cerebral glucose metabolism in older adults reporting significant memory concern

•We showed a significant APOE4*sex interaction for brain glucose metabolism in SMC.•Female APOE4 carriers showed higher cerebral glucose metabolism compared to female APOE4 non-carriers.•Male APOE4 carriers had lower cerebral glucose metabolism than male APOE4-noncarriers.•The effect of APOE4 on cerebral glucose metabolism is altered by sex in individual with SMC. There is accumulating evidence that the association of apolipoprotein E4 (APOE4) with the risk of developing Alzheimer’s disease (AD) is modified by sex. However, the associations of APOE4 status and sex with AD-related markers in older adults with significant memory concern (SMC) remain elusive. Among individuals with SMC (n = 106), we investigated the associations of APOE4 status and sex with multiple AD-related markers, including verbal memory, hippocampal volumes, cerebral glucose metabolism and cortical amyloid burden. In individuals with SMC, we found a significant APOE4*sex interaction for cerebral glucose metabolism, but not verbal memory, hippocampal volumes or cortical amyloid burden. Specifically, female APOE4 carriers showed significantly higher cerebral glucose metabolism compared to female APOE4 non-carriers whereas male APOE4 carriers had lower cerebral glucose metabolism than male APOE4-noncarriers. In conclusion, the effect of APOE4 on cerebral glucose metabolism is altered by sex in individuals with SMC.