Amyloid-beta A4 protein (Aβ) fibrils (Vascular Aβ)

Aggregated amyloid-beta (Aβ) fibrils in cerebral vessel walls are the defining pathological feature of Cerebral Amyloid Angiopathy (CAA), a condition that frequently co-occurs with Alzheimer's disease (Charidimou et al., 2017, Lancet Neurology). These fibrils, primarily composed of the Aβ40 isoform, deposit within the tunica media and adventitia of small to medium-sized arteries and capillaries in the leptomeninges and cerebral cortex (Greenberg et al., 2020, Nature Reviews Neurology). This deposition leads to the progressive destruction of vascular smooth muscle cells and the weakening of the vessel wall, which significantly increases the risk of lobar intracerebral hemorrhage and ischemic injury (Greenberg et al., 2014, Lancet Neurology). As a therapeutic target, vascular Aβ is addressed by monoclonal antibodies like Lecanemab and Donanemab, which are designed to clear amyloid aggregates from the brain (Van Dyck et al., 2023, NEJM). However, targeting these vascular deposits is associated with a high risk of Amyloid-Related Imaging Abnormalities (ARIA), including edema and microhemorrhages, due to the transient disruption of the blood-brain barrier during clearance (Sperling et al., 2011, Alzheimer's & Dementia). Understanding the clearance mechanisms of these aggregates is essential for developing safer treatments for neurodegenerative and neurovascular disorders.

Other names

Cerebral Amyloid Angiopathy (CAA) fibrilsVascular amyloid-betaAβ40 fibrilsAmyloid-beta peptide 1-40Amyloid-beta peptide 1-42

Monoclonal antibodies target specific epitopes on the aggregated amyloid-beta fibrils, which triggers their clearance through microglial-mediated phagocytosis or Fc-receptor-mediated transport across the blood-brain barrier (Sevigny et al., 2016, Nature). This process aims to reduce the amyloid burden in the cerebral vasculature and parenchyma to slow cognitive decline and prevent vascular rupture (Van Dyck et al., 2023, NEJM).