Organ-Brain Axis in Alzheimer's Disease: A Systemic Perspective on Pathogenesis and Progression

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and memory decline. Current therapeutic strategies largely provide symptomatic relief and remain limited in their capacity to halt or reverse disease progression. Accordingly, increasing efforts seek to reexamine AD pathophysiology from a systemic perspective and to identify novel therapeutic targets. Although classical AD research has focused primarily on intrinsic brain pathology, accumulating evidence indicates that disease progression reflects complex interactions among multiple cellular and systemic mechanisms. The central nervous system (CNS) is now recognized as functionally interconnected with peripheral organs through immune-mediated and neural communication networks. Within this framework, the concept of the organ-brain axis has emerged, proposing that organ-specific immune microenvironments and inflammation-derived mediators originating from peripheral tissues may modulate immune homeostasis in the brain, neuronal survival, and neurodegenerative processes. In patients with AD, immunological alterations are observed not only within the CNS but also in peripheral organs including the gut, lung, liver, and bladder, and these changes are associated with disease progression. Peripheral immune dysregulation extends beyond localized inflammatory responses, potentially contributing to sustained neuroinflammation, disruption of blood-brain barrier integrity, and pathological activation of microglia and astrocytes. Rather than viewing AD as a disorder confined to the brain, this review adopts a systemic perspective in which peripheral immune environments dynamically interact with central neuroinflammatory pathways. We comprehensively summarize immune cell alterations across major peripheral organs under AD pathology, their interactions with neuronal cells, and the potential signaling mechanisms that mediate organ-brain immune crosstalk.