Additional file 1: Supplemental Figure 1. Gut microbiome composition differs significantly between University of Chicago and Washington University in St. Louis. Analysis of bacterial α-diversity and β-diversity in fecal content from 9-week-old APPPS1-21 male mice collected at the University of Chicago and Washington University in St. Louis. (a) Shannon index, (b) Pielou species evenness. (d) PCoA plot generated by using unweighted unifrac distance metric. Diversity analyses, including alpha and beta diversity, alpha rarefaction, and group significance were analyzed by QIIME and QIIME2. Data are presented as mean SEM. Significance was determined using Two-way ANOVA . *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Supplemental Figure 2. GV-971 targets Aβ plaque halo in a sex-dependent manner. (a) Representative immunofluorescent images of HJ3.4+ Aβ (red) surrounding X34+ Aβ (blue). White * indicates regions of reduced plaque halo. (b,c) Quantification of an average number of HJ3.4 + Aβ surfaces within 5μM X34+ Aβ surface plaque in cortices of 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female = 9-12). Data are presented as mean SEM. Significance was determined using unpaired t-test (d). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Supplemental Figure 3. GV-971 alters amino acid metabolism. GC-nCI-MS and PFBBR derivtization heatmap analysis of metabolite abundance in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 4. GV-971 modifies tryptophan metabolism. LCMS/MS heatmap analysis of tryptophan pathway, indole pathway, and kynurenine pathway metabolite concentrations in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 5. GV-971 influences primary and secondary bile acid metabolism. LCMS/MS heatmap analysis of primary and secondary bile acid concentrations in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 6. GV-971 Significantly change peripheral and neuro-cytokine and chemokine production. Pie chart denoting the distribution of cytokine/chemokine production following GV-971 treatment. Chart is characterized into four groups based on expression levels compared to the control groups: Increased, Decreased, Not significant, and Non Detected. (a). Serum analyzed from the University of Chica...