Blood–brain barrier dysfunction and peripheral immune activation in Alzheimer’s disease: an inflammation-centered review

Abstract

Alzheimer’s disease (AD) is traditionally defined by amyloid-β deposition, tau pathology, synaptic failure, and progressive cognitive decline. However, growing evidence indicates that neurovascular dysfunction and systemic immune activation are not merely secondary consequences but active contributors to disease progression. The blood–brain barrier (BBB), as a dynamic immunovascular interface, regulates the communication between the central nervous system and the peripheral immune system. In AD, aging, amyloid-β toxicity, tau-related stress, vascular senescence, endothelial inflammatory signaling, pericyte injury, and gliovascular remodeling can weaken BBB integrity. Barrier disruption may then permit peripheral cytokines, chemokines, plasma-derived factors, monocytes, and T-cell–related signals to influence microglial activation, astrocyte reactivity, oxidative stress, synaptic dysfunction, and neuronal injury. Recent studies further suggest that peripheral monocytes may participate in amyloid-β clearance and transport, whereas chronic monocyte activation, adaptive immune remodeling, and T-cell exhaustion may amplify neuroinflammation. This review summarizes recent experimental and clinical evidence linking BBB dysfunction, peripheral immune activation, and AD progression. We propose an inflammation-centered model in which BBB breakdown and peripheral immune dysregulation form a pathogenic loop that accelerates neurodegeneration. Targeting this BBB–peripheral immune axis may provide new opportunities for biomarker development, patient stratification, and combination therapy beyond classical amyloid- and tau-directed strategies.