Cell-free DNA as a marker of progression in Alzheimer's dementia and its role in chronic inflammation
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PROJECT ABSTRACT/SUMMARY: Mild cognitive impairment (MCI) is defined as having impaired cognition in one or more domains with minimal limitations to daily life activities and may represent a timepoint at which interventions for Alzheimer’s disease (AD) can be implemented. However, there is significant variability in rates of progression from MCI to AD; therefore, it is critical to non-invasively identify individuals at highest risk of disease progression. One proposed marker of disease progression is cell-free DNA (cf-DNA), which is released from cell death processes. Measuring serum cf-DNA conveys information about cell death mechanisms that can help us better understand energy changes in the dying cells. Determining the connections between cf-DNA and immune system activation allows us to better recognize factors that contribute to chronic inflammation in MCI and AD. This study hypothesizes that increased cf-DNA levels in individuals with MCI are associated with faster rates of progression to AD, and that cf-DNA contributes to AD-associated chronic inflammation via activation of the nuclear factor kappa-B (NF- kB) pathway. Digital PCR will be used to measure cf-DNA levels in serum of individuals with MCI and normal cognition and associations with rates of cognitive decline will be studied (Aim 1). Differentiated human neuronal cell lines treated with purified cf-DNA from individuals with MCI and normal cognition will be evaluated for changes in inflammatory cytokine production, activation of NF-kB signaling, and cell death (Aim 2). This innovative study has the potential to identify important immune signaling pathways to examine further in the context of AD and can directly impact patient care by utilizing cf-DNA as a marker associated with rates of disease progression in individuals with MCI.
