Wednesday, January 15, 2025
1/15/2025
ABSTRACT The concept of the “microbiota-gut-brain axis” has advanced to current research that supports the hypothesis that the gut microbiome may be responsible for the cognitive decline seen in Alzheimer's Disease (AD). In our RF1 proposal we have: 1) built a cohort of 260 older adults and have been following them over time, collecting clinical and cognitive assessment data as well as biological samples in the form of stool and peripheral blood; 2) determined both microbiota taxonomy and gene function among these older adults; 3) utilized stool samples to determine how the microbiome can induced intestinal inflammation and how this correlates back to observed systemic inflammation; and 4) studied the microbiome metabolic product differences to explain how these products can influence microglia functioning. This cohort is comprised of older adults clinical diagnosed with AD (n=32), amnestic mild cognitive impairment (MCI) (n=48) or no cognitive problems (ND) (n=66). Among each of these classes we have subjects that have improved their cognitive testing over time, remained stable, or declined in cognition at different rates. Our central hypothesis is that there is a characteristic dysbiotic microbiome among AD older adults and that the level of inflammation-type dysbiosis positively correlates with both local and systemic inflammation and cognitive decline. Specifically, in Aim 1 we have been assessing characteristics of the AD patient's microbiome in comparison to older adults with MCI or ND and longitudinally assessed the microbiome composition and correlated it to changes in cognition. In Aim 2 we have been determining the extent of microbiome dysbiosis among AD patients, correlating this with the level of induce in vivo/vitro epithelial dysfunction, and then back to cytokine markers of inflammation and T cell population markers of immunosenescence. Finally, in Aim 3 we have been performing metabolomics to identify metabolite profile differences between AD patients, and both MCI and ND older adults and used identified metabolites in our in vivo/vitro assays to describe its effects on microglial functioning. This supplement is requesting additional funding to better characterize each group (AD, MCI, and ND) beyond clinical diagnosis and to include peripheral blood markers that can identify the pathology associated with AD. Use of blood biomarkers aligns with the more recently established NIA-AA Research Framework and movement in the field towards more biologic characterization of AD. We plan to measure concentrations of Aβ peptides and phosphorylated-tau, as well as ApoE proteotypes and neurofilament light chain levels from the peripheral blood. These biomarkers correlate well with concentrations in CSF and PET imaging, which are expensive and impractical to perform for every research participant. Our work is taking a critical step forward to bridge microbiome associations with AD to causality by showing how the AD associated microbiome dysbiosis can lead to systemic inflammation, inflammation-causing immunosenescence, and ultimately cognitive dysfunction. This additional funding would greatly strengthen our current findings and add new insight into pathologic mechanisms.
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