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Alzheimer's disease (AD) is a highly heterogeneous neurodegenerative condition. The current study identifies clinically relevant molecular subtypes of the early and late mild cognitive impairment (EMCI and LMCI) stage of AD using 401 patients' data from the ADNI consortium. We integrate patients' metabolomics data with the PBMC transcriptomics data using an unsupervised clustering method called Similarity Network Fusion (SNF), and identify 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 time to dementia diagnosis. We detected many dysregulated processes such as aminoacyl-tRNA biosynthesis, immune system activity, zinc imbalances, histidine metabolism, glutathione metabolism, glycerophospholipid metabolism, alanine, aspartate, and glutamate metabolism, and arginine biosynthesis. 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.

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