ABSTRACT Now nineteen years after 9/11, a high proportion of World Trade Center (WTC) responders show elevated mental and physical health effects that include a higher than expected burden of mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or a related dementia (ADRD). Because the potential for neurodegenerative diseases as indicated by MCI are concerning, there is a critical need to understand the pathogenesis of the disorder and identify biomarkers to facilitate early intervention before irreversible changes to the brain occur. Our pilot work revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI and the differentially expressed (DE) genes were enriched in pathways related to neuroinflammation. These findings are in line with evidence that monocytes play a pivotal role in mediating the interface between central and peripheral systems via transduction through the blood brain barrier. The proposed study builds on our pilot work by evaluating association between changes in monocyte transcriptome with changes in clinical phenotype and neuropathology over a 24-month period. Using our banked peripheral blood mononuclear cell (PBMC) and plasma samples on a subset of n=250 responders who have been genotyped (U01 OH011864), we will generate monocyte transcriptome profiles from PBMCs at an average sequencing depth of 150M reads per sample, as well as validated plasma markers of cerebral neuropathology (including pTau181, NfL, Aβ42, Aβ40) at both time points (baseline and 24-month follow up). Among these 250 responders, we also have structural and functional MRI neuroimaging for a subset of responders (n=120) from a separate study (U01 OH011314). In Aim 1, we will determine if changes in monocyte transcriptome (gene and alternative splicing (AS) levels) are associated with changes in clinical phenotype. In Aim 2, we will determine if changes in monocyte transcriptome are associated with changes in each plasma protein. Among the genes and AS associated with NfL, we will further determine if they are associated with cortical thickness by integrating the MRI data. In Aim 3, we will identify genetic variants associated with changes in monocyte transcriptome via eQTL and sQTL analyses. The proposed study will be the first to examine monocyte transcriptome and alternative splicing (AS) in individuals converting to dementia. The in-depth understanding of biological processes underlying the dynamics of monocytes in MCI and how the processes are associated with disease progression can help identify novel blood-based biomarkers for ADRD and intervention strategies that target relevant pathways early in the disease to prevent or slow the progression of neurocognitive disorders.