Microbial and Neurovascular Predictors for Subtypes of Prodromal Alzheimer's Disease - PROJECT SUMMARY Alzheimer's disease (AD) remains the most prevalent form of neurodegenerative dementia and presents a significant healthcare challenge. While the widely-accepted amyloid β (Aβ) cascade hypothesis posits that AD is caused by Aβ plaque buildup in the brain that leads to other pathological changes such as neurofibrillary tangles, substantial gaps in our knowledge persist in our understanding of the pathophysiological processes driving early cognitive decline and progression from prodromal to dementia stages of AD. Emerging evidence implicates the gut microbiota (GMB) and neurovascular dysfunction as early, interacting contributors to AD pathogenesis. Gut dysbiosis has been linked with Aβ, tau, and ApoEε4, and may promote neurovascular injury through chronic inflammatory processes. Neurovascular dysfunction, including reduced cerebrovascular reactivity (CVR), altered cerebral blood flow (CBF), and blood-brain barrier disruption, often precedes classical AD pathology, suggesting a key mechanistic role for the gut–neurovascular axis. To advance critical knowledge along this line, systematic human studies are urgently needed to explore the complex interactions between GMB, neurovascular dysfunction, AD biomarkers, and clinical progression. Our central hypothesis is that microbial agents (bacteria, viruses, and associated metabolites) exacerbate neurovascular dysfunction and cognitive decline in prodromal AD. In support of this, our pilot study compared prodromal AD to cognitively unimpaired control cohorts and demonstrated 1) discriminatory bacterial strains, including oral pathogens capable of modifying bile acids and other metabolites; 2) phages associated with bile acid-modifying bacteria and those potentially affecting immunity against pathogens; 3) negative associations between inflammation-inducing bacteria and cognitive functioning, as well as MRI neurovascular metrics of CVR and CBF; and 4) novel associations between MRI measures of neurovascular uncoupling (NVUC) and microbiome features. In this prospective longitudinal project, we will combine cognitive testing, MRI-based neurovascular imaging, and microbial/metabolite profiling. Aim 1 will define bacterial, viral, and metabolic signatures that predict cognitive decline. Aim 2 will determine how microbiome and neurovascular interactions predict cognitive trajectories using integrative statistical and computational modeling. This proposal represents a transformative approach to elucidate microbial-neurovascular drivers of AD. Through integration of longitudinal multi-omics and cognitive data with statistical causal inference methods, we will uncover potential microbial determinants and neurovascular pathways that drive disease onset and progression. By bridging microbial, vascular, and cognitive domains, this work has the potential to transform diagnostic testing and novel therapeutic approaches for delaying or preventing AD progression.
