Targeting the peripheral immune system for treatment of Alzheimer’s disease

Abstract Alzheimer’s disease (AD) has traditionally been viewed as a central nervous system (CNS)-restricted proteinopathy. Although this neurocentric focus has yielded fundamental insights; it may not fully capture the systemic complexity contributing to disease heterogeneity and therapeutic challenges. Accumulating evidence indicates that peripheral tissues and systemic immune processes actively contribute to AD pathology.This review synthesizes current research across four key themes: the peripheral origin of amyloid precursor proteins, the bidirectional transport of amyloid across the blood–brain barrier (BBB), the clinical trial pipeline for peripheral immunomodulation, and emerging peripheral cellular targets capable of modifying amyloid homeostasis. Systemic immunity offers a more accessible therapeutic route that bypasses the BBB, potentially mitigating the adverse side effects associated with central drug delivery. Numerous peripheral innate immune cells can serve as a dynamic pool for amyloid clearance, utilizing the peripheral "sink" mechanism through active BBB transport and glymphatic clearance. Notably, receptors like Complement Receptor 4 (CR4) exhibit a distinct capability to size-selectively recognize noxious amyloid aggregates while leaving monomeric clearance unaffected, presenting a sustainable long-term mechanism to halt disease progression. Ultimately, modulating systemic immune activity represents a promising new horizon to support amyloid clearance, reduce neuroinflammation, and improve cognitive outcomes.