Fig. 5

Ε4 carriers show lower energy expenditure, decreased oxygen consumption, and pro-glycolytic changes in the plasma metabolome. a, c Energy expenditure (EE) (a) and VO₂ (c) of female Ε4 carriers (purple) and Ε4 non-carriers (blue) during the glucose challenge. Values shown are means (lines) +/− SEM (shaded). (E4- n = 44, E4+ n = 27; *P < 0.05, Two-way ANOVA repeated measures) (b, d) Incremental area under the curve (AUC) of EE (b) and VO₂ (d) was determined by Ε4 carriage and further by respective APOE genotypes in all participants. (E4- n = 61, E4+ n = 33; E2/E4 n = 2, E2/E3 n = 10, E3/E3 n = 51, E3/E4 n = 28, E4/E4 n = 3) (*P < 0.05, **P < 0.01, unpaired t-test, two-tailed; #P < 0.05 One-way ANOVA). e, h Pathway impact analysis highlights pyruvate metabolism and glycolysis as pathways significantly altered by E4 carriage in human plasma at baseline (e), while multiple carbohydrate and lipid processing pathways are altered by E4 carriage following the glucose drink (h) (FDR < 0.01). f, i Volcano plots showing changes in plasma metabolites. Lactate was the most significantly altered metabolite by APOE genotype at baseline (f), while multiple metabolites differed post-glucose drink (i) (ANOVA, FDR < 0.05). g Lactate values in individual subjects as determined by GC-MS analysis. j Enrichment analysis highlights multiple metabolic pathways as significantly altered by E4 carriage following the glucose drink, including the top hit of ‘Warburg effect’. All comparisons are E4+ (n = 33) vs E4- (n = 61)