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Abstract Introduction Recent research has found that World Trade Center (WTC) responders in their mid‐50s have an elevated prevalence of mild cognitive impairment (MCI) that is associated with neural degeneration and subcortical thinning. This article extends our understanding of the molecular complexity of MCI through gene expression profiling of blood. Methods The transcriptomics of 40 male WTC responders were profiled across two cohorts (discovery: nine MCI and nine controls; replication: 11 MCI and 11 controls) using CITE‐Seq at single‐cell resolution in blood. Results Comparing the transcriptomic signatures across seven major cell subpopulations, the largest differences were observed in monocytes in which 226 genes were differentially expressed. Pathway analysis on the genes unique to monocytes identified processes associated with cerebral immune response. Discussion Our findings suggested monocytes may constitute a key cell type to target in blood‐based biomarker studies for early detection of risk of MCI and development of new interventions.