# Changes in monocyte transcriptome as a predictor of cognitive decline in WTC responders: a longitudinal study

> **NIH ALLCDC U01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $498,336

## Abstract

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.

## Key facts

- **NIH application ID:** 10312349
- **Project number:** 1U01OH012257-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** SEAN CLOUSTON
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** ALLCDC
- **Fiscal year:** 2021
- **Award amount:** $498,336
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312349

## Citation

> US National Institutes of Health, RePORTER application 10312349, Changes in monocyte transcriptome as a predictor of cognitive decline in WTC responders: a longitudinal study (1U01OH012257-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10312349. Licensed CC0.

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