Exploring the Gut Microbiome as a Promising Frontier in Alzheimer's Disease Therapy

Alzheimer's Disease (AD) is a major global health challenge, particularly in ageing populations, and current therapies offer limited modification of disease progression. Emerging evidence indicates that the gut microbiome contributes to AD pathogenesis through metabolic, immune, and neuroendocrine mechanisms. Microbial metabolites, including Short-Chain Fatty Acids (SCFAs), bile acids, and trimethylamine-N-oxide (TMAO), regulate neuronal signalling and blood-brain barrier integrity, and dysbiosis has been linked to amyloid-β (Aβ) accumulation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, and synaptic dysfunction. Host genetic factors, particularly APOE ε4 and immune-regulatory variants such as TREM2 and CD33, further influence microbial composition and susceptibility to metabolite-driven pathology. This review provides a deeper synthesis of current evidence by integrating findings across multi-omics studies and identifying key unresolved issues in the microbiome-AD field. The discussion evaluates whether microbiome alterations act as early initiators or downstream consequences of neurodegeneration, examines sources of heterogeneity in microbiome-targeted interventions, and considers how inter-individual variability in host genetics and microbial ecology may inform precision therapeutics. Conceptual frameworks presented here, including a two-phase dysbiosis trajectory and a metabolite "tipping-point" network, aim to reconcile conflicting results and support the development of testable mechanistic hypotheses. Microbiome-directed strategies, such as probiotics, prebiotics, dietary modulation, faecal microbiota transplantation, and antiviral therapies, demonstrate promise but require rigorous mechanistic validation and methodological standardisation. Continued advancement in longitudinal, genotype-stratified, and multi-omics research will be essential for translating microbiome science into clinically actionable approaches. Overall, current evidence positions the gut microbiome as a compelling frontier for the development of personalised, diseasemodifying strategies in AD.