The Alzheimer\'s Disease Metabolome: Effects of Sex and APOE ϵ4

Recent studies have provided evidence that late-onset Alzheimers disease (AD), the major cause of dementia in the elderly, can, at least in part, be considered a metabolic disease. Besides age, female sex and APOE {varepsilon}4 genotype represent strong risk factors for AD. At the same time, they both give rise to large metabolic differences, suggesting that metabolic aspects of AD pathogenesis may differ between males and females and APOE {varepsilon}4 carriers and non-carriers, respectively. Here, we systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 140 metabolites measured in serum samples of 1,517 individuals from the AD neuroimaging initiative with AD biomarkers for A{beta} and tau pathology, as well as neurodegeneration. We observed substantial sex differences in effects of 15 metabolites on AD biomarkers with partially overlapping differences for APOE {varepsilon}4 status groups. These metabolites highlighted several group-specific alterations that were not observed in unstratified analyses using sex and APOE {varepsilon}4 as covariates. Combined stratification by both variables uncovered further subgroup-specific metabolic effects limited to the group with presumably highest AD risk, i.e. APOE {varepsilon}4+ females. Pathways linked to the observed metabolic alterations suggest that females experience more expressed impairment of mitochondrial energy production in AD than males. These findings indicate that dissecting metabolic heterogeneity in AD pathogenesis may allow for grading the biomedical relevance of specific pathways for specific subgroups. Extending our approach beyond simple one or two-fold stratification may thus guide the way to personalized medicine.