Sex-specific metabolomics-derived blood biomarkers of Alzheimer’s disease

Readily accessible diagnostic tools are crucial for early detection of Alzheimer’s disease (AD). Here, we sought to identify peripheral metabolism biomarkers of cerebral AD pathology. Untargeted liquid chromatography-mass spectrometry was used to quantify 2286 serum metabolites in participants on a longitudinal memory clinic study. Unbiased between-group analysis using Orthogonal Partial Least Squares Discriminant Analysis, Linear Discriminant Analysis and Principal Component Analysis were performed to build a classifier for AD as indicated by CSF biomarkers. MetaboAnalyst was subsequently used for selection of the most relevant metabolites; pathway enrichment was performed to determine biological pathway alterations related to AD. No biomarker signature was found in the whole cohort. Stratification according to sex allowed building a classifier for AD using 14 metabolites in males and 9 in females that significantly improved the prediction of the presence of AD compared to a reference model. Thirteen enriched pathways were identified, including lipid and amino acid metabolisms. Compared to a reference model, the selected metabolites significantly improved the prediction of cognitive decline in females. Sex-specific peripheral metabolism biomarkers are useful to predict cerebral AD pathology and cognitive decline, and detect related pathway alterations. This highlights the need for personalised diagnostic and therapeutic approaches in AD.