Cerebrovascular disease and the pathophysiology of Alzheimer's disease. Implications for therapy

Abstract

Dementia is a disease of the elderly, and although there are many causes of dementia, Alzheimer's disease (AD) and vascular dementia (VaD) account for the majority of cases world- wide. Many patients with dementia have radiological and neuropathological features of AD and VaD, with the classical neurofibrillary tangles and senile amyloid-beta (Abeta) plaques of AD together with the cerebral infarcts of VaD. In this review we examine the close relationship between AD and VaD and suggest that the age changes in cerebral blood vessels that are the basis of cerebrovascular disease and VaD may also be responsible for the failure of elimination of Abeta from the brain in AD. Abeta appears to be eliminated along the perivascular pathways by which interstitial fluid (ISF) drains from the brain (effectively the lymphatics of the brain). In aged individuals, insoluble Abeta amyloid fibrils are deposited in the ISF drainage pathways resulting in cerebral amyloid angiopathy (CAA). We review the evidence that age changes in cerebral arteries and cerebrovascular disease inhibit the perivascular drainage of ISF and Abeta along the walls of cerebral arteries resulting in the accumulation of insoluble and soluble Abeta in the brain in AD. Therapies for AD are reviewed, especially those involving immunotherapy for the removal of insoluble Abeta from the cerebral cortex and the facilitation of drainage of ISF and soluble Abeta from the brain.