Stage-Dependent Plasma Metabolomic Signatures for Discriminating Alzheimer’s Disease and Multiple Mild Cognitive Impairment Subtypes

Background/Objectives: Despite Alzheimer’s disease (AD) and mild cognitive impairment (MCI) metabolic implications, the metabolic alterations underlying different cognitive impairment stages and their relationships with amyloid pathology remain insufficiently understood. Here, this study aims to identify and validate stage-dependent plasma metabolomic signatures for discriminating between AD and MCI subtypes and to determine their associations with brain Aβ deposition. Methods: We quantitatively profiled plasma metabolites of participants in two independent Chinese Han cohorts (n1 = 226, n2 = 80). Differential metabolic signatures among AD, multi-domain MCI (mdMCI), amnestic MCI (aMCI), and normal cognition (NC) groups were identified using integrated univariate, multivariate, pathway and classification analyses. Diagnostic biomarker panels were established using machine learning algorithms. The associations between stage-specific metabolic biomarkers and brain Aβ burden as measured by amyloid PET were assessed. Results: In cohort 1 (87 AD, 61 mdMCI, 40 aMCI, 38 NC), 25, 20, and 16 differential metabolites were identified, mainly involving amino acids, bile acids, fatty acids, and neurotransmitters. These signatures enhanced AD stratification beyond demographics and APOE-ε4. Diagnostic panels (8, 8, 6 metabolites) were validated in cohort 2. Moreover, associations between metabolic biomarkers and regional Aβ deposition were stage-specific. Stronger correlations of neuronal, bile acid, and acylcarnitine-related metabolites with Aβ deposition in brain regions were found in AD patients, weaker and spatially restricted in MCI subtypes. Conclusions: Our findings underscore that AD is a metabolic disease and emphasize potential diagnostic biomarkers in AD and multiple MCI subtypes within the analyzed sample of older Chinese Han adults, indicating the utility of plasma metabolites as further diagnostic and therapeutic targets.