The Gut-Brain Axis: Exploring the Role of Gut Microbiota in Alzheimer's Disease Pathogenesis and Therapeutics

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, and cognitive decline. Increasing evidence implicates the gut-brain axis as a key regulator of AD pathogenesis through immune, metabolic, and neuroendocrine pathways.

This review systematically synthesizes recent preclinical and clinical studies investigating the role of gut microbiota in AD, focusing on microbial composition, mechanistic communication pathways, and microbiota-targeted therapeutic strategies.

Gut microbiota dysbiosis contributes to AD progression through multiple mechanisms, including activation of TLR4/NF-κB-mediated neuroinflammation, disruption of blood-brain barrier integrity, and altered microbial metabolite production, particularly short-chain fatty acids (SCFAs) and tryptophan-derived compounds. These changes influence amyloid deposition, tau phosphorylation, and synaptic dysfunction.

Gut microbiota dysbiosis plays a significant role in AD progression by promoting neuroinflammation, BBB dysfunction, and altered microbial metabolite production. Microbiota-targeted interventions, such as probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have the potential to modulate these pathways and improve cognitive outcomes, although results vary across studies.

The gut microbiota acts as an upstream regulator of AD pathology through interconnected molecular mechanisms. However, variability in study design, limited clinical validation, and lack of standardized protocols remain major challenges. Future research should focus on mechanistic validation using multi-omics approaches and the development of personalized microbiome-based therapeutic strategies.