Author Identifier
Date of Award
2026
Keywords
preclinical Alzheimer’s disease, gut microbiome, amyloid-β (Aβ) pathology, shotgun metagenomics, short-chain fatty acids (SCFAs), metagenomic pathways, dietary patterns
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
W.M.A.D. Binosha Fernando
Second Supervisor
Ralph Martins
Third Supervisor
Stephanie Rainey-Smith
Fourth Supervisor
Thilini Jayasinghe
Fifth Supervisor
Karen Scott
Abstract
There is growing interest in how changes in gut microbial composition, microbial metabolic activity, and gut derived metabolites may contribute to pathological changes during the preclinical stage of Alzheimer’s disease (AD). Gut microbes and their metabolites, particularly short-chain fatty acids (SCFAs), play important roles in regulating inflammation, metabolism, and communication between the gut and the host.
Previous studies have observed gut microbial dysbiosis across the AD continuum, including reductions in SCFA producing taxa and changes in microbial profiles in individuals with mild cognitive impairment and AD. Altered faecal SCFA concentrations have also been associated with inflammatory and metabolic changes related to amyloid pathology. However, most evidence is derived from symptomatic populations and relies primarily on taxonomic analyses. Few studies have examined gut microbial composition in cognitively unimpaired adults stratified by cerebral amyloid-β (Aβ) status. Consequently, findings across existing studies remain inconsistent and, in some cases, inconclusive, thereby limiting understanding of gut microbial alterations occur ring during the preclinical stage of AD.
In addition to microbial composition, gut-derived metabolites and microbial metabolic pathways provide critical insight into microbial activity that cannot be determined from taxonomy alone. Emerging evidence suggests that SCFA and functional pathways may be altered in AD. However, most studies have examined metabolites or pathways separately, and relatively few have used shotgun metagenomic sequencing to characterise functional pathways alongside quantitative assessment of faecal SCFA concentrations, particularly during early amyloid accumulation. As a result, metabolic and functional changes during preclinical AD remain poorly understood.
To address these gaps, this thesis used shotgun metagenomic sequencing to exam ine gut microbial composition, faecal SCFA concentrations, and microbial metabolic pathways in cognitively unimpaired adults stratified by cerebral Aβ status (Aβ Low and Aβ High) from highly characterised cohorts. This approach allowed comprehensive evaluation of microbial composition, SCFA associations, and functional metabolic pathways relevant to early AD pathophysiology.
The results showed that cerebral amyloid status was associated with significant differences in gut microbial composition in cognitively unimpaired adults. Specific microbial taxa also varied across the AD continuum and between Aβ Low and Aβ High groups, indicating that microbial dysbiosis may be present prior to the onset of cognitive symptoms. Associations between faecal SCFA concentrations and microbial taxa also differed according to amyloid status. In addition, relationships between SCFA concentrations and microbial metabolic pathways were distinct between amyloid groups, indicating alterations in microbial metabolic activity during the preclinical stage of AD.
Dietary patterns were subsequently examined as modulators of gut microbial composition, faecal SCFA concentrations, and microbial metabolic pathways, a relationship that has not been previously examined in preclinical AD. Healthier dietary patterns were associated with saccharolytic metabolism and SCFA production, whereas West ern dietary patterns were linked to alternative fermentation processes and lower SCFA production. These associations varied between Aβ Low and Aβ High groups, high lighting potential interactions between diet, gut microbiota, and amyloid pathology.
In summary, this thesis demonstrates that gut microbial dysbiosis, SCFA related alterations, and differences in microbial metabolic activity are associated with cerebral amyloid accumulation prior to cognitive impairment. By analysing species level meta genomic profiling, functional pathways, quantitative SCFA measurement, and dietary assessment in an amyloid stratified, cognitively unimpaired cohort, this work provides novel insight into gut related mechanisms in preclinical AD. These findings support further longitudinal and interventional studies targeting diet and the gut microbiome to improve early identification and prevention strategies for AD.
Access Note
Access to this thesis is embargoed until 1st July 2031
Recommended Citation
Udeshini Dissanayaka, D. (2026). Gut microbiome composition, metabolic activity, and dietary associations in preclinical Alzheimer’s disease. Edith Cowan University. https://doi.org/10.25958/m2z5-0755