Gut-Brain Homeostatic Continuum framework proposes a multi-layered system for understanding Alzheimer disease pathogenesisNew Framework Suggests Gut Health Links to Alzheimer's Disease

The gut-brain axis has substantially improved our understanding of Alzheimer’s disease (AD) by highlighting the complex bidirectional interactions between the gastrointestinal tract, the microbiota and the central nervous system. Nevertheless, this framework does not fully explain why brain and organismal homeostasis can be maintained for decades despite the continuous and cumulative burden of aging, genetic susceptibility and environmental stressors, or why this resilience ultimately fails in some individuals. In this review, we propose the Gut-Brain Homeostatic Continuum (GBHC), a conceptual framework that extends the classical gut-brain axis into a dynamic, interconnected system of layered homeostatic mechanisms. Rather than viewing gut-brain interactions as parallel signaling routes, the GBHC emphasizes how the preservation of intestinal and blood-brain barrier integrity supports coordinated immune, metabolic and inter-organ regulation, which in turn contributes to systemic proteostasis and the trafficking and clearance of proteins. Through these interconnected processes, peripheral physiological states may influence the capacity of the brain to maintain homeostasis and resilience. Within this framework, AD is viewed as a progressive erosion of organismal resilience rather than the consequence of a single pathological pathway. We discuss how aging, genetic factors and the exposome may progressively challenge interconnected regulatory mechanisms, weakening the capacity to preserve homeostasis and increasing vulnerability to neurodegeneration. This perspective also suggests a complementary approach to biomarker discovery, focusing on multimodal signatures that capture biological trajectories and changes in regulatory capacity. Such signatures could integrate markers of barrier integrity and permeability, immune and metabolic regulation, microbial and host-derived metabolites, extracellular vesicle cargo, and proteostasis-related proteins, including established markers of neurodegeneration such as amyloid-β, phosphorylated tau and neurofilament light chain. Although several aspects of the GBHC remain hypothetical and require experimental validation, this framework provides an integrative model that complements current concepts of AD pathogenesis and opens new perspectives for multidisciplinary research and therapeutic innovation.