Sex and APOE ε4 genotype modify the Alzheimer's disease serum metabolome

Abstract

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

Fig. 1. Sex-based effect heterogeneity of metabolites in relation to A-T-N biomarkers.

Scatter plots showing Z scores of effect estimates of metabolite associations with A-T-N biomarkers for males (x axis) versus females (y axis). Homogeneous effects (i.e., those with same effect direction and comparable effect size) are located close to the diagonal, heterogeneous effects are located close to the anti-diagonal, and sex-specific effects are located close to the x axis for male-specific and y axis for female-specific effects. Homogeneous overall significant results are drawn as diamonds, effects with significant heterogeneity are drawn as rectangles, and effects significant in only one sex are drawn as triangles. Metabolites additionally marked by an asterisk are significant in one sex only and simultaneously show significant heterogeneity. Sex-specificity is further illustrated by a color scale (blue: females; green: males). On the upper right panel, example boxplots of metabolite residuals (obtained by regressing out included covariates) for each effect type are shown separately for females and males with (in dark red) and without (in light red) CSF Aβ_1–42 pathology, respectively. Source data are provided as Source Data File.

Fig. 2. Group-specific association of proline levels with brain glucose uptake in APOE ε4-carrying females.

Boxplots showing residuals of proline levels (derived by regressing out covariate effects) for a the full sample; b onefold stratification by sex; c onefold stratification by APOE ε4 status; and d twofold stratification by both sex and APOE ε4 status; separately for high (light blue) and low (darker blue; derived by mean-split) FDG-PET values. The only subgroup showing a significant difference in proline levels are APOE ε4+ females with substantially higher levels in participants with lower brain glucose uptake. This Bonferroni-significant subgroup-specific effect (P = 8.2 × 10⁻⁵ in covariate-adjusted linear regression) would have been missed in sex/APOE ε4 genotype-adjusted analyses applying no or onefold stratification. Source data are provided as Source Data File.