Dual roles of complement in cerebral amyloid angiopathy: A two-compartment framework across the blood–brain barrier

Complement is increasingly recognized as a context-dependent contributor to cerebral amyloid angiopathy (CAA), yet its roles are often discussed without compartmental resolution and are frequently extrapolated from Alzheimer's disease (AD). This review synthesizes evidence from human pathology, multi-omics, and experimental models to delineate how complement activity diverges between the vessel wall/perivascular space (PVS) and the brain parenchyma, and how the two compartments couple when the blood–brain barrier (BBB) is compromised. In the vessel wall/PVS, where Aβ40 deposition coincides with endothelial stress and access to circulating proteins, complement activation can be sustained and may progress to terminal pathway engagement. Available data link membrane attack complex (MAC) formation to vessel wall injury, BBB disruption, microbleeds, and impaired intramural periarterial drainage (IPAD), reinforcing vascular Aβ accumulation. Classical pathway signals are consistently detected in CAA vessels, while lectin pathway co-activation and alternative pathway amplification likely contribute to persistent activation at the vascular interface. In the parenchyma, terminal outputs appear more constrained and pathogenic effects are more often mediated by C1q/C3 opsonization and C3a/C5a receptor signaling that sustains glial inflammatory circuits and synaptic vulnerability, secondarily destabilizing the BBB and facilitating spillover. CAA-related inflammation and anti-Aβ therapy-associated ARIA highlight periods of amplified vascular inflammation that expose these injury programs. Finally, we outline a compartment- and stage-specific therapeutic framework that prioritizes reducing terminal pathway burden and MAC-driven vascular injury while limiting parenchymal inflammatory amplification and preserving early opsonophagocytic clearance, supported by spatial biomarkers and CAA-specific models. • CAA and AD evidence indicates compartment-specific complement effector outputs in vessels/PVS versus parenchyma. • Complement-centered mechanisms provide a framework to interpret ARIA and CAA–AD comorbidity. • BBB disruption and impaired IPAD are key drivers of bidirectional vascular–parenchymal complement crosstalk. • A compartment- and stage-informed view of complement in CAA helps prioritize therapeutic targets and strategies.