Mechanistic roles and therapeutic potential of gut microbiota–neuroimmune crosstalk in the development and progression of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and distinct neuropathological and biological alterations, including amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and neuronal loss. Increasing evidence suggests that dysregulated neuroimmune responses are closely associated with AD progression and may provide an important interface through which the gut microbiota influences brain homeostasis. Gut microbial dysbiosis and alterations in microbial functional output have been reported in patients with AD and mild cognitive impairment, although current human evidence remains predominantly associative. Experimental and animal studies further suggest that microbial structural components, microbiota-derived metabolites, and long-distance communication signals, including bacterial extracellular vesicles and microbial nucleic acids, may modulate intestinal barrier integrity, peripheral immunity, cerebrovascular interfaces, and central glial responses, thereby potentially influencing Aβ clearance, tau pathology, and synaptic function. Conversely, AD-associated alterations in neuroimmune regulation, autonomic signaling, neuroendocrine function, and mucosal immunity may reshape the intestinal ecological niche and further modify microbial composition and function, supporting a bidirectional gut microbiota–neuroimmune regulatory network. In this review, we integrate these interactions within a stage-oriented conceptual framework encompassing disease susceptibility, pathological initiation, amplification, and chronic progression, while emphasizing that these stages represent overlapping biological processes rather than established clinical categories. We also evaluate microbiota-based interventions, including dietary strategies, prebiotics, probiotics, psychobiotics, postbiotics, fecal microbiota transplantation, next-generation probiotics, engineered microorganisms, and metabolite-targeted approaches, with explicit consideration of their distinct evidence bases, translational limitations, and safety concerns. Overall, gut microbiota–neuroimmune crosstalk provides an integrative framework for understanding systemic contributions to AD pathophysiology, but establishing causal relevance in humans will require longitudinal studies, mechanistic validation, and population-stratified clinical trials.