Project Overview-Globally, populations are ageing increasing the prevalence of Alzheimer’s disease (AD), due to lack of effective treatments. The traditional Mediterranean diet, rich in fiber and polyphenols (PPs) can help prevent or delay cognitive dysfunction and preserve healthy brain structure and function. Cognitive decline is inversely associated with higher PP intakes (>421mg/day) i.e., total flavonoids, flavan-3-ols and flavonoid oligomers. The positive brain effects of flavonoid intake are likely mediated in part by gut microbial PP metabolites, consistent with the emerging role of the brain-gut microbiome (BGM) system in neurodegeneration. Our preliminary data indicate that circulating phenyl-γ-valerolactones (PVL), neuroprotective compounds exclusively produced by gut microbiota from flavan-3-ol rich foods are associated with delaying cognitive dysfunction. Intake of PPs change gut microbial composition and function, altering the physiology of the host’s secondary bile acid (BA) pool through modulation of bacterial 7α-dehydroxylation of de-conjugated primary BAs into secondary BAs. This is noteworthy as 7α-dehydroxylation of BAs does not happen in the brain and because gut microbial BA metabolites have regulatory and signaling functions in the brain. The ratio between certain primary and secondary BAs is also dysregulated in AD with significantly lower serum concentrations of cholic acid (a primary BA) and increased levels of deoxycholic acid (a bacterially produced secondary BA). The increased ratio of cholic acid to deoxycholic acid is correlated with cognitive decline. Increased levels of tyrosine, tryptophan, purine, and tocopherol have also been identified in postmortem AD brains. However, specific pathways and mechanisms underlying these associations are unclear. In this multi-PI application by leaders in the field of BGM interactions, we leverage the collectively (NIH, HSC, SFI) funded Tripartite US‐Ireland R&D Partnership Program to determine the mechanisms involved in PP intake on maintaining healthier cognitive and brain function, as mediated by gut microbiota metabolites of PP and BAs in 50+ year old elderly with enhanced AD risk. We will conduct a year long, randomized double blind placebo-controlled trial in 400 at AD-risk elderly in the US and Northern Ireland. We will use translational human-animal models, meta and transcriptomic interrogation of gut microbiome, targeted and untargeted metabolomics, multimodal brain imaging, assessment of cognitive function and inflammatory status, and advanced bioinformatics techniques to test the following Specific Aims: Aim A: Identify the protective effects of dietary PP supplementation on brain and cognitive parameters in high AD risk participants. Hypothesis (H)A1. PP intake compared to placebo (PLA) will lead to less brain volume loss, decreased white matter hyperintensities (reflecting improvements in measures of myelination, axonal loss, glia atrophy, and efficacy in synaptic transmission), and alterations in anatomical and functional connectivity of affected brain regions (e.g., pontine locus coeruleus, dorsal raphe nucleus, and hippocampus). HA2. PP intake compared to PLA will result in improved executive functioning (inhibition, working memory, flexibility) and will be associated with cortical and subcortical brain network changes in affected brain regions. Aim B: Determine the effect of PP intake on the microbiome, inflammatory, and AD biomarkers in high AD risk participants. Hypotheses: PP intake compared to PLA results in: HB1. Improved fecal microbial and tryptophan-related metabolite profiles, and a reduced ratio of cholic acid to deoxycholic acid, altered BA metabolism. HB2. Altered global metabolic activity of gut microbiota. HB3. Increased plasma levels of microbial PP metabolites. HB4. Decreased plasma levels of inflammatory markers (C-reactive protein, tumor necrosis factor-alpha, interleukins [IL-1β, IL-6]). HB4. Decreased novel AD specific blood plasma markers such as ptau181, ptau217 (modified versions of tau protein in AD brain scans), glial fibrillary acidic protein (GFAP), and neurofilament light chain (protein reflecting neuronal death). Aim C: Measure causal relationships between PP intake and gut microbial metabolites, inflammatory and AD markers, brain parameters, and cognitive function. Hypotheses: Using bioinformatics and machine learning approaches: HC1. The PP-related changes in gut microbial pathways, circulating PP metabolites and decreased inflammatory and AD markers will mediate the improvements in brain structure, function, and connectivity, and in executive function. Aim D: Utilize a reverse translational approach to identify changes in mouse brain and behavior by PP-induced alterations in the human gut microbiome. Hypotheses HD1. Fecal microbiome transplantation from high AD risk participants on a high PP intake, displaying altered fecal microbial and tryptophan-related metabolite profiles, BA metabolism, and global metabolic activity of gut microbiota, will be reconstituted in a mouse model. HD2 Resulting gut-microbiome changes will differentially influence murine brain and cognitive parameters. Impact: Establishing the molecular mechanisms associated with the protective effects of PP intake on cognitive function, with an emphasis on BGM interactions, can help develop effective dietary regimes to prevent or delay onset of AD in at-risk elderly thereby reducing cognitive decline and healthcare costs.
