The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid β (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in mice that express human APOE4 allele and overexpress Aβ (E4FAD mice). Another goal of the study was to identify potential pharmacogenetic differences in response to Rapa between the E4FAD and E3FAD mice, mice with human APOE ε3 allele. We found that in E4FAD mice, Rapa normalized body weight, restored CBF (especially in females), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observed in E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain than E4FAD-Rapa mice. Further, Rapa appeared to normalize lipid-associated metabolism in E4FAD mice but slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice.
