Alzheimer's disease has long been treated as a disease confined to the brain — but mounting evidence suggests the brain is in constant, disease-shaping dialogue with the rest of the body. Understanding the molecular couriers that carry signals across this divide could fundamentally change how clinicians approach both early detection and intervention in AD.
This comprehensive review, published in the Journal of Nanobiotechnology, synthesizes evidence for extracellular vesicle (EV)-mediated bidirectional signaling across six major organ-brain axes: liver-brain, heart-brain, gut-brain, lung-brain, bone-brain, and adipose-brain. EVs are nanoscale membrane-bound particles shed by virtually all cell types, capable of transporting bioactive cargo — proteins, lipids, nucleic acids, and metabolites — across biological barriers including the blood-brain barrier. The review evaluates how organ-derived EVs may modulate neuroinflammation, disrupt neurovascular integrity, and influence amyloid-β and tau processing. Critically, it also examines the reverse direction: how brain-derived EVs (BDEVs) may alter peripheral organ physiology. The authors conclude that the gut-brain, liver-brain, and adipose-brain axes currently hold the strongest empirical support, while pathways such as the bone-brain and lung-brain axes remain largely at the preclinical or mechanistic stage.
This review arrives at a pivotal moment in AD research, as single-organ models have repeatedly failed to fully explain disease heterogeneity or treatment resistance. The EV framework is compelling precisely because it offers a mechanistic bridge between well-established systemic risk factors — metabolic syndrome, gut dysbiosis, cardiovascular disease — and central neurodegeneration. However, several key limitations temper enthusiasm: much of the axis-specific evidence derives from animal models or in vitro systems, EV isolation methodologies remain inconsistent across studies, and causal directionality is difficult to establish in observational human data. The translational applications the review highlights — EVs as diagnostic biomarkers in blood or CSF, or as engineered drug-delivery vehicles crossing the blood-brain barrier — are genuinely promising but years from clinical validation. Overall, this is a valuable synthesis that reframes AD as a systemic disease and points toward multi-organ diagnostic and therapeutic strategies, though the field needs larger, longitudinal human cohort studies to move from mechanistic plausibility to clinical utility.