To determine inflammatory analytes that predict clinical progression and their biological role in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer’s disease (AD).

Increasing evidence suggests that inflammatory pathways may regulate AD progression. There is still a lack of clarity as to which specific immunological analytes predict cognitive decline in AD, the pathobiological role, and at what stage of the disease they are noted.

A longitudinal study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort over 15 months, with replication in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort over 36 months. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts along with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau). The ability of inflammatory analytes to predict clinical progression along clinical dementia rating scale- sum of boxes (CDR-SB) and Mini mental state exam (MMSE) were assessed and the gene ontology (GO) terms related to key biological processes related to the significant analytes identified.

CCL2 was consistently noted to predict longitudinal cognitive decline in both the discovery and ADNI cohorts in the CSF, even after accounting for age, sex, education, APOE ε4 status and baseline cognitive scores.  The panel of additional inflammatory analytes that met correlation significance thresholds in both cohorts were found to be related to natural killer inflammatory cell chemotaxis in the CSF and responses to interferon-gamma and leukocyte differentiation in the plasma in a GO term analysis.

Cytotoxic immunity, as inferred from expressed cytokines in the plasma and CSF, may play a crucial role in clinical progression among MCI-AD patients.