Apolipoprotein E Genotype-Dependent Nutrigenetic Effects to Prebiotic Inulin for Reducing Risk for Alzheimer’s Disease in a Mouse Model

Abstract

Abstract Objectives Apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD). Cognitively normal APOE4 carriers show an early decline in brain metabolic functions and gut microbiome dysbiosis before the onset of AD compared to APOE3 carriers. Our laboratory previously found that inulin, a prebiotic, is effective to restore metabolic functions and gut microbiome balance, and thus reduce risk for AD in an ApoE4 mouse model. However, whether the responses to the inulin are APOE allele-dependent remains unknown. Therefore, our objective was to identify whether inulin would differently contribute to metabolic and gut microbiome changes due to APOE genotypes. Methods We fed 3-month-old asymptomatic ApoE3 (E3FAD) and ApoE4 (E4FAD) mice prebiotic inulin or cellulose as a control for 4 months (N = 60; Male: Female = 1:1). After 4 months, we used magnetic resonance spectroscopy to measure in vivo brain scyllo-inositol level, a compound that has been demonstrated to inhibit amyloid β aggregation. We collected the fecal samples for gut microbiome sequencing, and cecal and blood samples for metabolomic profiling. Results Inulin induced scyllo-inositol in hippocampus of the brain with a higher level in E4FAD mice. Inulin increased blood metabolites in tryptophan and tyrosine metabolic pathways that enhance nervous system in E3FAD mice. It increased blood metabolites in pentose phosphate pathway and citric acid cycle that support nucleotides and nucleic acids biosynthesis and energy production in E4FAD mice. These alterations in hippocampus and blood showed inulin's impacts on systemic metabolism depending on mouse ApoE genotypes. Inulin enhanced short chain fatty acids in cecum with a greater increase in E3FAD mice. E3FAD mice showed more distinct gut microbiome patterns between inulin and control groups compared to E4FAD mice. Conclusions Inulin-induced systemic metabolism and gut microbiome changes are APOE genotype-dependent. Future studies can design human interventions that may facilitate the guide of personalized nutrition in AD prevention. Funding Sources This research was supported by grants from NIH, NIH/CTSA, and American Federation for Aging Research to A-LL and NIH/NIDDK to JDH and LMY. The 7T ClinScan small animal MRI scanner was funded by the S10 NIH Shared Instrumentation Program Grant.