Integrated Metabolomics and Transcriptomics Analysis Identifies Molecular Subtypes within the Early and Late Mild Cognitive Impairment Stages of Alzheimer’s Disease

Abstract

AbstractAlzheimer’s disease (AD) is a highly heterogeneous neurodegenerative condition. The current study identified clinically relevant molecular subtypes of the early and late mild cognitive impairment (EMCI and LMCI) stages of AD using 401 patients’ data from the ADNI consortium. We integrated patients’ metabolomics data with the PBMC transcriptomics data using an unsupervised clustering method called Similarity Network Fusion (SNF), and identified two subtypes in early and late MCI patients, respectively. The differences between these subtypes’ metabolite concentrations and gene expression well correlate with physio-pathogenesis for AD, based on cognitive measurements, pseudo-trajectory analysis, and longitudinal analysis of dementia diagnosis. We detected many dysregulated processes between subtypes, such as aminoacyl-tRNA biosynthesis, immune system activity, zinc imbalances. While immune-related pathways are commonly dysregulated pathways in EMCI and LMCI stages, oxidative stress is prevalent in EMCI, whereas metabolic abnormality is enriched in LMCI. Refined subtypes within EMCI and LMCI are a step-forward toward more personalized treatment strategies for progressing patients before AD diagnosis.