Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease

Roy O Weller, Stephen D Preston, Malavika Subash, Roxana O Carare

Amyloid is deposited in the walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) in the brains of older individuals and of those with Alzheimer disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-beta (Abeta) from the brain along perivascular lymphatic 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 cerebrospinal fluid. In this review we focus on the pathology and pathogenesis of CAA, its role in the aetiology of AD and its impact on immunotherapy for AD. The motive force for lymphatic drainage of the brain appears to be generated by arterial pulsations. Failure of elimination of Abeta along perivascular pathways coincides with a reduction in enzymic degradation of Abeta, reduced absorption of Abeta into the blood and age-related stiffening of artery walls that appears to reduce the motive force for lymphatic drainage. Reduced clearances of Abeta and CAA are associated with the accumulation of insoluble and soluble Abetas 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 Abeta 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 Abeta from the brain. Increased knowledge of the physiology and structural and genetic aspects of the lymphatic drainage of Abeta from the brain will stimulate the development of therapeutic strategies for the prevention and treatment of AD.