Microbiome-targeted Alzheimer’s interventions via gut-brain axis

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited treatment options, underscoring the need for novel therapeutic targets. The gut-brain axis has emerged as a critical bidirectional communication system, with growing evidence establishing gut dysbiosis as a causal factor in AD pathogenesis. This dysbiosis, characterized by a reduction in beneficial microbes and an increase in pro-inflammatory taxa, compromises intestinal and blood–brain barrier integrity, promoting systemic inflammation and the translocation of neurotoxic agents like lipopolysaccharide (LPS). Consequently, the balance of key microbial metabolites is disrupted, reducing neuroprotective short-chain fatty acids (SCFAs) and indoles while elevating inflammatory mediators, which collectively exacerbate neuroinflammation, amyloid-β (Aβ) deposition, and tau pathology. This review evaluates promising interventions, including probiotics, anti-inflammatory diets, exercise, and phytochemicals that can restore microbial balance, enhance barrier function, and improve cognitive outcomes in preclinical and early clinical studies. However, clinical translation is hindered by an overreliance on animal models, short-term studies, and insufficient mechanistic insight. Future research must prioritize large-scale human trials, multi-omics integration to elucidate signaling pathways, and personalized approaches that account for host genetics and baseline microbiome composition to fully harness the therapeutic potential of the gut-brain axis for AD.