Sex-Dependent Responses to Prebiotic Inulin in Cerebral Blood Flow and Scyllo-Inositol Metabolism in APOE Mice

Apolipoprotein E4 (APOE4) is the most potent genetic risk factor for Alzheimer's disease (AD). Early dietary intervention might be critical for preventing AD progression for APOE4 carriers. Here we investigate whether, in APOE4 carriers, a prebiotic inulin diet can preserve cerebral blood flow (CBF) and increase brain scyllo-inositol, a therapeutic compound that has been proved to inhibit amyloid-beta (Aβ) aggregation and alleviate the risk of AD, and whether the responses to inulin are sex-dependent, compared with risk-neutral APOE3 carriers. Four-month-old, asymptomatic APOE3 and APOE4 mice were fed inulin or a cellulose control diet for four months (N = 18/group; Male: Female = 1:1). CBF and scyllo-inositol were measured by magnetic resonance imaging (MRI) and MR spectroscopy, respectively, at the end of the study. We performed a 3-way ANOVA (gene ⋉ diet ⋉ sex) followed by post hoc Tukey's multiple comparisons test using GraphPad Prism. A p < 0.05 was considered statistically significant. Inulin increased CBF in the APOE4 male mice in the whole brain (p < 0.001), hippocampus (p = 0.043), cortex (p = 0.016), and thalamus (p < 0.001), but these differences were not found in female mice. In contrast, inulin increased brain scyllo-inositol in APOE4 female mice (p = 0.006), as well as in both sexes in APOE3 mice (male, p < 0.001; female, p < 0.001). These findings suggest that the responses to inulin diet are sex- and APOE genotype-dependent in preserving CBF and scyllo-inositol metabolism (markers of brain functionality), indicating a nutrigenetic difference between male and female mice. This study may provide valuable insights into precision nutrition in AD prevention in the future. This research was supported by grants NIH/NIA RF1AG062480 to ALL. The 7T ClinScan small animal MRI scanner was funded by the S10 NIH Shared Instrumentation Program Grant.