Understanding the “Microbiome-gut-brain axis” in Alzheimer’s disease and its Role in Cognitive Decline - 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.
