Sex and APOE \u03b54 genotype modify the Alzheimer\u2019s disease serum metabolome

Matthias Arnold,Gabi Kastenmüller,J Will Thompson,P Murali Doraiswamy,Michael W Weiner,Colette Blach,Gregory Louie,Jon B Toledo,Kwangsik Nho,Eugenia Trushina,David A Bennett,Kevin Huynh,Alexandra Kueider‐Paisley ,Roberta Dı́az Brinton ,Rima Kaddurah‐Daouk ,Xianlin Han,Lisa St John-Williams ,Peter J Meikle,Siamak Mahmoudiandehkordi,Ralph N Martins ,M Arthur Moseley,Jessica D Tenenbaum,Andrew J Saykin,Barbara Brauner,Tyler Massaro,Rui Chang,Jan Krumsiek,John Q Trojanowski,Leslie M Shaw,Rebecca Baillie

doi:10.1038/s41467-020-14959-w

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.

Highlights

Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease
Using metabolomics data from 1517 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts, we investigated how sex modifies the associations of representative A-T-N biomarkers[54,55] (A: cerebrospinal fluid (CSF) Aβ1–42 pathology; T: CSF p-tau; N: region of interest (ROI)-based glucose uptake measured by [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET)) with 139 blood metabolites using stratified analyses and systematic comparison of effects between men and women
We included all individuals with respective data regardless of diagnostic classification, as we were interested in these three representatives of the A-T-N AD biomarker schema[54,55] as our main readouts

Summary

Introduction

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 give rise to large metabolic differences. Complexity is added by studies showing a significant sex difference in effects of the APOE ε4 genotype, the strongest common genetic risk factor for LOAD These studies report risk estimates for ε4 carriers being higher in females, a finding that seems to be dependent on age[8,9,10,11,12,13]. Overall risk for mild cognitive impairment (MCI), the prodromal stage of AD, is higher in males[20,21], whereas progression to AD occurs faster in females, at least partly in APOE ε4-dependent ways[3,8,10,19,22,23] The mechanisms underlying this sex-linked and partly intertwined age- and APOE ε4-dependent heterogeneity in AD susceptibility and severity are only beginning to unravel, calling for novel approaches to further elucidate molecular sex differences in AD risk and biomarker profiles.

Methods

Results

Conclusion