APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD). Pre-symptomatic APOE4 carriers have developed neurovascular deficits decades before amyloid beta (Aβ) aggregation. Here we show that with Rapamycin treatment for 16 weeks, pre-symptomatic APOE4 mice had restored cerebral blood flow (CBF) and attenuated anxiety, compared to those of APOE3 mice. The CBF restorations were particularly significant in female mice or those with APP transgene. As Rapamycin and MRI and are readily to be used in humans, the findings may provide valuable information for future clinical trials to prevent AD for APOE4 carriers.