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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.

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