Changes in monocyte small noncoding RNAs as a predictor of cognitive decline in mild cognitive impairment and Alzheimer's disease

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ABSTRACT Twenty years after 9/11, the World Trade Center (WTC) responders show elevated rates mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or AD-related dementia (ADRD). MCI is often regarded as an intermediate stage between normal aging and dementia; thus it provides a window of opportunity to understand the pathogenesis of the disorder and identify factors that lead to the conversion of MCI to dementia. Epigenetic vulnerability and gene-environment interactions have been implicated in the etiology of ADRD. In particular, small noncoding RNAs (sncRNAs) have been shown to be promising biomarkers and provide insights into its pathophysiology. Preliminary findings further revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI; 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. Despite this, there is no study which has investigated the epigenetic regulation by sncRNAs in monocyte subpopulation that may explain how these changes affect downstream gene expression and proteins associated with AD neuropathy and disease progression. This proposal builds on the preliminary findings in monocyte transcriptome and capitalizes on existing biobank and clinical data by evaluating monocyte sncRNA via smRNA-seq in a subset of 100 responders over a 24-month period. The proposed study will determine if changes in monocyte sncRNAs are associated with changes in clinical phenotype; and identify the gene targets of sncRNAs in monocyte subpopulation associated with cerebral neuropathology. To enhance the impact of this study, an exploratory aim is included to identify a multi-omic signature by integrating monocyte sncRNAs, mRNAs and plasma proteins that predicts changes in clinical phenotype. This study would be the first to examine the synergy between monocyte sncRNAs, mRNAs and plasma proteins in individuals converting to dementia. Findings from this study will shed light on regulation of monocyte responses in disease progression, help identify novel blood-based biomarkers that may inform treatment efforts.