Uncovering etiological roles for microbial pathogens in the development of Alzheimer's disease (AD)

Myat N. Thwe

doi:10.17918/00011467

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the leading cause of dementia worldwide. Despite decades of research, the precise etiology of AD remains unresolved, and currently available therapies provide only limited symptomatic benefit without halting disease progression. Increasing evidence has challenged the long-standing assumption that the human brain is sterile, leading to the emergence of the brain microbiome/pathobiome and infection hypotheses of AD. Collectively, these theories propose that chronic microbial colonization, dysbioses, and host-pathogen interactions may contribute to neuroinflammation, amyloid-beta accumulation, tau pathology, and progressive neurodegeneration. This dissertation investigates the potential etiological role of microbial communities in Alzheimer's disease through spatial microbiome profiling, comparative neurobiobank analyses, and a phylogenetic comparative genomic characterization of Cutibacterium acnes, a prevalent pathogen found predominantly in AD brains vs. age-matched control brains. Chapter 1 provides a comprehensive review of Alzheimer's disease pathogenesis with emphasis on the infection hypothesis, neuroinflammation, blood-brain barrier dysfunction, and the emerging role of bacterial, viral, and fungal pathogens in neurodegeneration. Moreover, it details the potential contribution of Cutibacterium acnes as an opportunistic neuroinflammatory pathogen that we have repeatedly observed to be associated with AD brain tissue. Chapter 2 evaluates whether microbial signatures detected in postmortem brain tissues represent authentic tissue-associated microbiota or postmortem contamination. Using full-length 16S rRNA sequencing and microspatial edge-versus-core sampling approaches, microbial communities were analyzed in Alzheimer's disease and age-matched control (AMC) brain tissues. The findings demonstrated nearly complete overlap between edge and core microbial profiles, supporting the conclusion that the observed microbial signals are unlikely to arise from surface contamination during autopsy handling. Differential abundance analyses further identified microbial taxa enriched in AD-associated brain tissues. Chapter 3 expands this investigation through comparative microbiome profiling among independent neurobiobanks from the University of Arkansas, the University of Wisconsin and the University of Washington. Full-length 16S rRNA sequencing revealed modest regional and institutional variation while demonstrating mostly overlapping microbial community structures across cohorts. Beta diversity analyses identified partial clustering patterns associated with diagnosis, anatomical location, and institutional cohort, whereas alpha diversity measurements showed broadly comparable richness and diversity among cohorts. These findings support the reproducibility of microbial signatures across independently collected postmortem AD and AMC brain specimens and further reinforce the concept of a brain-associated microbiome in AMC and a brain-associated pathobiome in AD. Chapter 4 involved a large-scale pan-genome analysis and comparative genomic analysis of > 430 C. acnes genomes for which the tissue site of recovery was documented. Included in the analysis were twelve deep tissue isolates that I sequenced These analyses were performed to determine if C. acnes displays a phylopathogenic character in which there exists a phylogenetic clade structure that overlays the tissue site of clinical strain recovery. Whole-genome sequencing demonstrated substantial phylogenetic diversity among isolates recovered from anatomically distinct sterile tissues. Pan-genome analysis revealed an open accessory genome containing variable loci associated with adhesion, biofilm formation, oxidative stress responses, restriction-modification systems, and mobile genetic elements. Core genome phylogeny and average nucleotide identity analyses showed that deep tissue isolates were distributed across multiple phylogenetic lineages rather than forming a single tissue-specific clade. Virulence factor analyses further demonstrated lineage-dependent variability in accessory virulence-associated genes. Finally, Chapterlette 1 extends these investigations beyond Alzheimer's disease by characterizing microbial communities in postmortem Lyme disease brain tissues using full-length 16S rRNA sequencing. This exploratory study addresses the limited understanding of microbial composition in neurologically affected Lyme disease brain specimens and highlights the broader relevance of microbial community profiling of brains in neuroinflammatory disorders. In summary, this dissertation provides evidence supporting the existence of complex microbial communities within postmortem human brain tissue and establishes rigorous methodological approaches for distinguishing authentic microbial signals from contamination artifacts. The combined findings support a potential role for microbial dysbiosis and opportunistic pathogens in neurodegenerative disease pathogenesis, particularly in Alzheimer's disease. These studies contribute to the growing field of neurodegenerative microbiome research and provide a foundation for future investigations into microbial-based diagnostic, preventive, and therapeutic strategies for AD and related neurological disorders.

Uncovering etiological roles for microbial pathogens in the development of Alzheimer's disease (AD)

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Uncovering etiological roles for microbial pathogens in the development of Alzheimer's disease (AD)

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