A Comprehensive Review on the Microbial Signatures and Metabolic Mechanisms Underlying the Gut-Alzheimer's Disease Axis.

Alzheimer's disease (AD) is the most common form of dementia, driven by complex interactions among aging-related biological changes, neuronal degeneration, mitochondrial dysfunction, and environmental factors. Despite extensive research, effective disease-modifying therapies remain unavailable. Increasing evidence highlights the gut-brain axis as an important contributor to AD pathogenesis, particularly through amyloid-producing gut microbes that promote immune activation, neuroinflammation, and cerebral amyloid accumulation. This review summarizes current evidence linking gut microbiota (GM) dysbiosis to AD, focusing on microbial metabolites, neuroinflammatory pathways, and microbiota-targeted therapeutic strategies. A systematic analysis of experimental and clinical studies reveals that altered gut microbial composition is associated with systemic and neuroinflammation, blood-brain barrier dysfunction, oxidative stress, and neuronal damage. Key microbial metabolites, including short-chain fatty acids and indole derivatives, exhibit neuroprotective effects by regulating immune responses, maintaining barrier integrity, and supporting neuronal energy metabolism; disruption of these metabolites may accelerate neurodegeneration. Microbiota-based interventions such as probiotics, prebiotics, dietary modification, and fecal microbiota transplantation show beneficial effects in preclinical models by restoring microbial balance and reducing neuropathological features, although clinical evidence in humans remains limited. Overall, current findings support a contributory role of gut dysbiosis in AD and suggest that targeting the GM may offer a promising complementary strategy for disease modification and future therapeutic development.