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Objective: To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration., Methods: A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR-SB change over two years (≥3 points)., Results: Cerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL-10 pathway dysregulation. The ROC curves for ≥3 points change in CDR-SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different., Interpretation: Baseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL-10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI-AD. CCL2's utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)