Apolipoprotein E4 and immune dysfunction in Alzheimer's disease: mechanisms and therapeutic implications.

Emerging evidence suggests that apolipoprotein E4 (APOE4) functions as an organizer of brain-periphery immune crosstalk, coupling maladaptive microglial states with peripheral immune remodeling to establish a self-reinforcing neuroimmune loop that may accelerate the progression of Alzheimer's disease. In the central nervous system, APOE4 pushes microglia away from homeostatic surveillance toward metabolically stressed, inflammatory, and synaptotoxic phenotypes, thereby weakening pathological protein clearance and promoting neurodegeneration. In the periphery, APOE4 primes innate and adaptive immune cells toward a pro-inflammatory state, creating a reservoir that can communicate with the diseased brain and infiltrate it. In addition, APOE4 erodes the separation between central and peripheral immune compartments, enabling bidirectional immune crosstalk that amplifies neuroinflammation and neurodegeneration. In this review, we synthesize evidence for APOE4-driven central and peripheral immune dysregulation; discuss therapeutic opportunities for targeting the APOE4 immune axis; and highlight the need for human-derived, longitudinal, cross-tissue studies to identify causal, stage-specific, and targetable immune nodes for precision intervention.