Clearance pathways for Amyloid-β. Significance for Alzheimer’s disease and its Therapy

Deposition of amyloid in the walls of arteries as cerebral amyloid angiopathy (CAA) is present in 30% of individuals over 60 years and in over 90% of patients with Alzheimer’s disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-β (Aβ) from the brain along perivascular drainage pathways. In the absence of conventional lymphatic vessel in the brain, interstitial fluid and solutes drain from the brain to cervical lymph nodes along narrow basement membranes in the walls of capillaries and arteries, a pathway that is largely separate from the CSF. In this series we focus on the methods of elimination Aβ form the brain and how this is reflected in the dynamics of the CSF physiology. We address the enzymatic degradation of Aβ and its clearance into the blood, by perivascular macrophages, microglia and via the cerebrovascular basement membranes.

Reduced clearance of Aβ and CAA are associated with the accumulation of insoluble and soluble Aβ in the brain in AD and the probable loss of homeostasis of the neuronal environment due to retention of soluble metabolites within the brain. Tau metabolism may also be affected. Immunotherapy has been successful in removing insoluble plaques of Aβ from the brain in AD but with little effect on cognitive decline. One major problem is the increase in CAA in immunised patients that probably prevents the complete removal of Aβ from the brain. Increased knowledge of the physiology, structural and genetic aspects of the clearance of Aβ from the brain, as well as the dynamics of CSF, will stimulate the development of new biomarkers and efficient therapeutic strategies for the prevention and treatment of AD.