Gut-brain relationship in dementia and Alzheimer's disease: Impact on stress and immunity

Alzheimer’s disease (AD) is increasingly recognized as a condition shaped not only by central nervous system pathology but also by complex, bidirectional interactions between the gut, brain, and immune system. This review synthesizes emerging evidence on gut-brain-immune dysregulation in AD, with particular attention to how chronic stress, microbial imbalance, and neuroimmune signaling converge to influence disease risk and progression. We move beyond traditional microbiome-focused perspectives to incorporate non-microbial gut-derived mediators, including enteroendocrine hormones, bile acids, and vagal neuropeptides, which contribute to immune modulation, neurotransmission, and brain homeostasis. Importantly, we highlight that AD-related neurodegeneration can also feedback to impair gastrointestinal function and microbial composition, creating a self-reinforcing pathological loop. The review integrates recent findings on the role of host genetic polymorphisms, such as APOE4 and TREM2, in modulating gut permeability, immune tone, and microbiota profiles—emphasizing a systems biology model in which genome-microbiome interactions shape AD susceptibility. We also explore how single-cell omics technologies and multi-organ frameworks are redefining our understanding of gut-brain-immune circuits at cellular resolution. The translational section critically evaluates current and potential therapeutic strategies, including dietary, microbial, behavioral, and endocrine interventions, while addressing the challenges of applying preclinical findings to diverse human populations across the disease spectrum. By incorporating age-, stage-, and genotype-specific considerations, this review offers a comprehensive and timely synthesis of the gut-brain-stress axis in AD, positioning it as a key frontier in mechanistic research and precision therapeutic development.