Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease

Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-beta (A beta) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of A beta deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain-effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble A beta is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble A beta. Failure of perivascular drainage of A beta and deposition of A beta in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of A beta-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, A beta and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of A beta and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.