Research provides substantial evidence that late-onset Alzheimer's disease (AD), the major cause of dementia in the elderly, is a metabolic disease. Besides age, female sex and APOEε4 genotype represent strong risk factors for AD, and at the same time, give rise to large metabolic differences. Our systematic investigation of sex and APOE ε4 genotype differences in the link between metabolism and measures of pre-symptomatic AD using stratified analysis revealed several group-specific metabolic alterations that were not observed without sex and genotype stratification of the same cohort. Pathways linked to the observed metabolic alterations suggest females are more affected by impairment of mitochondrial energy production in AD than males, highlighting the importance of tailored treatment approaches towards a precision medicine approach.
AbstractRecent studies have provided evidence that late-onset Alzheimer's 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 ε4 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 ε4 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 Aβ 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 ε4 status groups. These metabolites highlighted several group-specific alterations that were not observed in unstratified analyses using sex and APOE ε4 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 ε4+ 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. Alzheimer's Association; Alzheimer's Drug Fund and the Karen L. Wrenn Trust. PMD has served as an advisor to and or received grants from companies for other projects. PMD also owns shares or serves on the board of companies whose products are not discussed here. PMD is also a co-inventor on patents in this field through Duke University which are unlicensed.