Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease

Alzheimer disease (AD) and cerebrovascular accidents (CVA) are the two leading causes of age-related demen-tia. The risk of AD, stroke, and CVA are known to increase at comparable rates with age. Recent advances on several fronts suggest that the vascular risk factors, which are linked to cerebrovascular disease and stroke in the elderly, significantly increase the risk of AD. Although some vascular lesions (eg, cerebral amyloid angiopathy, endothelial degeneration, and periventricular white matter lesions) are evident in most AD cases, fully one third of these cases will exhibit cerebral infarcts. Despite the interpretation of pathological evidence, longitudinal clinical studies suggest that stroke and AD occur in tandem more often than by chance alone. Strokes often occur in patients with AD and have been linked to the pathogene-sis of dementia. Nevertheless, the nature of this relationship remains largely unexplored. Irrespective of the ultimate pathogenic mechanism, these findings suggest that managing vascular disease is important in the treatment and prevention of AD or mixed dementia. Increasing evidence supports the notion that the underlying mechanism responsible for CVA is also responsible for AD-related dementia. The implicated pathogen-esis, which is primarily responsible for both disease processes , seems to involve chronic hypoperfusion. Hypop-erfusion appears to induce chronic oxidative damage in tissues and cells, largely due to the generation of reactive oxygen and reactive nitrogen species (ROS and RNS, respectively). Any condition, which outpaces the capacity of endogenous redox systems to neutralize such toxic inter-mediates, leads to a system imbalance or to major compensatory adjustments that rebalance the system. This new redox state is generally referred to as " oxidative stress " and is associated with other age-related degenerative disorders , such as atherosclerosis, ischemia/reperfusion, and rheumatic disorders. Chronic injury stimuli can also induce hypoperfusion in the microcirculation of vulnerable brain regions. Many common disease risk factors may underlie and play key roles in the development of cardiovascular, cere-brovascular, and neurodegenerative diseases. For example , it has been widely accepted that hypercholesterolemia is a risk factor for the development of cardiovascu-lar and cerebrovascular disease as well as AD. Vascu-lar insufficiency/hypoperfusion also is considered to be a pathogenic factor in the development of AD. Further, the positive relationship between cerebrovascular diseases, such as stroke and especially cerebrovascular atheroscle-rosis, indicates that the latter may also be linked to the pathogenesis of AD. In addition, ischemia/reperfusion induce chronic hypoxic conditions, which cause the formation of a large amount …