Dataset Information

Sex and APOE ?4 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 ?4 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 ?4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ?4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ?4+ 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.

SUBMITTER: Arnold M

PROVIDER: S-EPMC7052223 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Arnold Matthias M Nho Kwangsik K Kueider-Paisley Alexandra A Massaro Tyler T Huynh Kevin K Brauner Barbara B MahmoudianDehkordi Siamak S Louie Gregory G Moseley M Arthur MA Thompson J Will JW John-Williams Lisa St LS Tenenbaum Jessica D JD Blach Colette C Chang Rui R Brinton Roberta D RD Baillie Rebecca R Han Xianlin X Trojanowski John Q JQ Shaw Leslie M LM Martins Ralph R Weiner Michael W MW Trushina Eugenia E Toledo Jon B JB Meikle Peter J PJ Bennett David A DA Krumsiek Jan J Doraiswamy P Murali PM Saykin Andrew J AJ Kaddurah-Daouk Rima R Kastenmüller Gabi G

Nature communications 20200302 1

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 metaboli ...[more]

PMID: 32123170

Similar Datasets

Project description:Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Dataset Information

Sex and APOE ?4 genotype modify the Alzheimer's disease serum metabolome.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets