An association with great implications: vascular pathology and Alzheimer disease.

Elucidating the pathogenesis of sporadic Alzheimer disease (AD) remains an elusive goal despite decades of intense research. Sporadic AD is an emergent pathology that arises from a dynamic interplay of multiple genetic and environmental factors, set against a background of senescence-related changes. The dominance of the amyloid hypothesis tends to eclipse other possible AD pathogenic mechanisms. Drawn by the quasi-celestial morphology of amyloid plaques, their universality in AD, and the success of biochemical and transgenic approaches to their study, we have perhaps forgotten that the brain is entirely dependent on an efficient circulatory system. Vascular disease, with its resultant age-related hemorheologic decline, may have significant and perhaps even disproportionate impacts on sporadic AD development. A large body of evidence indicates that in many instances the cerebral arteries are morphologically altered and dysfunctional in AD. It is not farfetched to hypothesize that some cases of AD dementia may actually result from a chronic brain hypoperfusion. A computerized literature search of the topic ‘‘Brain Hypoperfusion and AD’’ listed over 100 publications, all suggesting a significant degree of brain hypoxia/ischemia in AD. Recent reports, using phase contrast MRI, found that total cerebral blood flow, representing the summation of both internal carotid and basilar arteries combined, was significantly decreased in AD patients (mean: 443 mL/min) relative to that of non-demented age-matched individuals (mean: 551 mL/min; P < 0.001). By contrast, the average cerebral blood flow in a young control group (median age 29 years) was 742 mL/min. At present, cardiovascular disease is the most common cause of morbidity and mortality in the older population. The etiology of brain hypoperfusion in the elderly and AD subjects is probably multifactorial and associated with the individual’s distinctive path of cardiovascular system decline. It can also result or be compounded by associated conditions, including hypertension, hypotension, myocardial infarction, valvulopathies, arrhythmias, heart failure, cardiomyopathies, endocarditis, and peripheral vascular disorders that are likely to alter cardiovascular function and cardiac output. Among the vascular disorders, atherosclerosis, with consequential arterial stenosis, is a widespread disease in the aged. By age 85, atherosclerosis is present in 100% of the population to some degree, mostly affecting the large arteries of the body and the coronary arteries as well as the arteries of the circle of Willis and major cerebral vessels. In some elderly individuals severe cerebral atherosclerosis and/or arteriosclerosis will occlude the vascular lumen to the extent of jeopardizing brain perfusion. The deleterious effect of lipid and connective tissue deposition in the arterial walls is complicated by calcification and ensuing rigidity that will increase both peripheral vascular resistance (the steady component) and vascular impedance (the pulsatile component), further compromising brain hemodynamics. A key issue that has confronted researchers since Alzheimer’s time is whether or not there is a causal relationship between cerebral artery pathology and AD dementia. This issue was apparently resolved in the late 1960s by a series of investigations that found a lack of consistency in the coincidental occurrence of cerebral atherosclerosis and dementia. In recent years, however, the issue has resurfaced, as a considerable body of evidence has clearly shown that risk factors and markers of atherosclerotic vascular disease, including hypertension, coronary artery disease, myocardial infarction, hypercholesterolemia, hyperhomocysteinemia, diabetes, smoking, and obesity are likewise risk factors for AD. New studies have unequivocally demonstrated that major artery intracranial stenosis has a strong statistical association with dementia and the specific histopathology of AD. The clinico-pathologic correlative study of Honig et al was based on data collected at the National Alzheimer’s Coordinating Center, which serves the 32 National Institutes on Aging AD research centers. Multivariate analysis of data from 1054 subjects demonstrated that the degree of atherosclerosis of the arteries of the circle of Willis was strongly correlated with both clinical dementia and neuritic plaque density. Thus, circle of Willis stenosis is associated not simply with dementia but also with a specific indicator of AD, the amyloid plaque. These results corroborated previous investigations that were performed at Sun Health Research Institute (SHRI). In the first of these, computerized image analysis of crosssections of the circle of Willis arteries from 54 consecutive autopsy cases, including 32 AD and 22 non-demented (ND) elderly controls, revealed that the degree of arterial stenosis was significantly increased in the AD subjects. In the AD group, 87 of 391 (22%) examined arteries were over 80% occluded, whereas only 13 of 277 (5%) were as extensively blocked in the ND group (P < 0.001). Most of the cross-sectional arterial lumenal occlusions were clearly due to yellow deposits of atheroma plaques characteristic of atherosclerosis. In some instances, however, the reduction in lumenal surface was defined by arteriosclerosis characterized by the hyaline, symmetrical accumulation of connective tissue in the intima and tunica media. The degree of arterial stenosis was positively and significantly correlated with neuritic plaque density, Braak stage, and cerebral white matter rarefaction. A second study indicated that AD subjects also have significantly greater narrowing of the major leptomeningeal arterial branches of the circle of Willis. In a third and larger study, a total of 215 subjects were investigated, representing consecutive AD and ND control cases coming to autopsy at SHRI between 1999 and 2003. Ninety-two AD cases (60%) exhibited moderate to severe stenosis and 62 cases (40%) were classified as having zero to mild lumenal narrowing. By contrast in the ND group 12 cases (20%) had moderate to severe stenosis and 49 (80%) had zero to moderate obstruction (P < 0.0001). A significant correlation between atherosclerosis, the presence of dementia, and the density of AD histopathology was also observed by the