Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer’s disease pathogenesis

Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA), is common in advanced age and even more common in Alzheimer’s disease. CAA may be complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal dominant CAA also show propensity for intracerebral hemorrhage, due to germline mutations in specific amyloidogenic precursor proteins and apparent compromise of structural integrity of the blood vessel wall due to marked amyloid deposition. The relationship between cerebral amyloid angiopathy and cognitive dysfunction, however, is less clear. While cognitive dysfunction in familial CAA is likely related to prodigious amyloid deposits and vascular luminal compromise (e.g., hereditary cerebral hemorrhage with angiopathy—Dutch type (HCHWA-D)), cerebral amyloid angiopathy with intracerebral hemorrhage often presents sporadically in cognitively intact elderly patients. Moreover, while about 80% of subjects with Alzheimer’s disease have demonstrable amyloid β within blood vessel walls at autopsy, the vast majority of these fail to suffer clinically relevant intracerebral hemorrhage during life. The remaining 20% manage to progress and die of their disease with virtual no amyloid within blood vessels. Thus, the role of amyloid β deposits in cerebral vessels as regards cognitive function on the one hand, and tendency for hemorrhage on the other, remain to be resolved for sporadic late onset Alzheimer’s disease and CAA. Recent studies on transgenic APP23 mice suggest a relationship between passive immunization and amyloid angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage was unclear from the data presented. We suggest that amyloid accumulation represents a response to chronic stress, and that the neurodegenerative process occurs at the neuronal level, encompassing oxidative stress and aberrant cell cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt perturbation of this balance (e.g., amyloid β immunization) is deleterious.