Cerebral amyloid angiopathy and dementia

Cerebral amyloid angiopathy (CAA) is a fundamental part of the pathology of many disorders causing dementia and/or cerebral haemorrhage. In Alzheimer's disease (AD), CAA is due to the deposition of amyloid alpha protein (Abeta) within the adventitia and media of leptomeningeal and brain parenchymal arteries. Although virtually all cases of AD show CAA to a greater or lesser extent, the brain distribution of CAA is not uniform with the occipital lobe being the most commonly and most severely affected region. In vessels affected by CAA, local muscle and elastic elements are lost and replaced by amyloid fibrils, thereby weakening the overall structure of the vessel. Consequently, CAA predisposes towards cerebral infarction and cerebral haemorrhage, though the clinical affects of CAA in AD are mostly silent, or at least are ''masked'' by the greater degree of neuronal dysfunction induced by senile plaque (SP) formation and neurofibrillary degeneration. Nonetheless, major cerebral infarctions with focal neurological deficits can occur in some cases of AD, and CAA is a major cause of fatal intracerebral (lobar) haemorrhage. CAA may also contribute to white matter lesions (myelin loss) in AD by inducing ischaemia through autoregulatory dysfunction. Although the Abeta protein deposited within blood vessels in AD is similar in chemical composition to that deposited in the brain parenchyma in SP, there is no clear relationship between the 2 pathologies. Indeed, when CAA is high, SP formation may be low, and vice versa. As if to emphasise these differences, Abeta within CAA is mostly Abeta40 whereas that within SP is Abeta42. Such compositional differences may reflect differences in source, with Abeta in SP being derived from nerve cells and Abeta in CAA having a local vascular origin. Although certain inherited forms of CAA with cerebral haemorrhage are associated with autosomal dominant mutations in APP and other genes (cystatin-C, transthyretin, gelsolin, ABrit, ADan), in most cases of AD CAA does not associate clearly with any genetic risk factor other than APO E beta4 allele, which appears to increase the severity of CAA in a dose dependent manner, especially within the occipital cortex. Genotype/phenotype correlations may be helpful in understanding the development of CAA in AD and other disorders. Why blood vessels in the occipital lobe should be most susceptible to CAA in AD remains unclear, though this pattern of blood vessel involvement does not seem to be recapitulated in other disorders in which CAA is the principal pathological change.