Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.