Cerebral amyloid angiopathy: Amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease

Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid β (Aβ) in cortical and leptomeningeal vessel walls. Although it has been suggested that Aβ is derived from vascular smooth muscle, deposition of Aβ is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Aβ in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Aβ accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Aβ occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease.