Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease: Pro-CAA position statement

For the purposes of this debate here we argue the case that cerebral amyloid angiopathy (CAA) has a direct role in the pathogenesis of Alzheimer’s disease (AD). Firstly, there is a very close relationship between CAA and AD and they share genetic risk factors. Secondly, we propose a specific mechanism which puts age-related cerebrovascular degeneration at a crucial point in the pathogenesis of AD as follows. Amyloid β-protein (Aβ) is normally eliminated from the brain along with extracellular fluid by bulk flow along the perivascular pathway. Age-related fibrosis of cerebral cortical and meningeal arteries leads to impaired drainage of Aβ along the perivascular pathway and, together with the production of Aβ by smooth muscle cells and perivascular cells, is responsible for accumulation of Aβ as CAA. Reduced elimination leads to increased concentration of soluble Aβ in the extracellular fluid of the brain parenchyma. Increased concentration of soluble Aβ leads to the formation of insoluble Aβ plaques, other features of AD pathology, and dementia.