Genetic investigations suggest that the amyloid-beta (Aβ) peptide has a central role in Alzheimer's disease (AD). However, genetically determined familial AD is rare, while sporadic AD is the most common form of this dementia. Nearly 25 years after the Aβ molecule was identified as a potential therapeutic target, the exact cause(s) of AD dementia remains undefined. For the foreseeable future the standard pharmacologic treatments are virtually palliative, offering only steadily diminishing functional maintenance without hope of cure.
Alzheimer's disease may result from the combined and chronic, cascading effects of multiple systemic diseases affecting the elderly, among them cardiovascular, immune/inflammatory, endocrine and ultimately a dysfunctional brain energy metabolism. In recent years, a broad body of evidence derived from epidemiologic, correlative and experimental studies has strongly linked atherosclerotic vascular disease (AVD) with AD (reviewed in reference [1
]). Postmortem studies have recently shown that individuals with AD have significantly more atherosclerotic narrowing of the intracranial arteries [1
Despite the epidemiological and neuropathological evidence, the question of whether intracranial AVD has a significant causal role in AD pathogenesis still remains unanswered, although there are data consistent with causation. As atherosclerosis generally begins much earlier in life than AD, the temporal relationship suggests that AVD may cause or accelerate AD, rather than the reverse. Results from several longitudinal life-history studies have shown that elevated AVD risk factors in midlife are associated with increased AD risk in old age [6
]. Individuals with higher midlife cholesterol levels have a higher risk of developing AD, and patients with clinically or neuropathologically diagnosed AD have higher cholesterol levels compared to non-demented control (NDC) individuals [8
]. There is also considerable evidence from experimental studies suggestive of a causative effect for increased blood cholesterol. The production of APP and the Aβ peptide, the main biochemical AD marker, in cell culture and animal models is regulated by cholesterol and decreased by cholesterol-lowering drugs such as statins, and some molecular mechanisms have been proposed for these interactions (reviewed in reference [13
]). The independent association of AD with multiple AVD risk factors suggests, however, that cholesterol is not the sole culprit in dementia.
That hypercholesterolemia, hypertension, diabetes, hyperhomocysteinemia, tobacco smoking and other AVD risk factors would produce pathology through completely separate molecular mechanisms seems improbable. A common mechanism may be hypoperfusion. The circulatory system is preeminent in the development of the brain and the maintenance of its vital functions. Thus, any pathology that impedes circulation, including the normal age-related decline in cardiovascular function and its increasing inability to adapt and repair is deleterious. Consequently, the importance of recognizing the interrelationship between cardiovascular disease and brain perfusion in AD cannot be overstated.
Ischemic brain disease is the generic designation for a group of closely related syndromes resulting from a disparity between the supply (perfusion) and the demand imposed by the brain for oxygenated blood. In addition, it involves reduced availability of nutrient substrates and ineffective removal of CO2
and noxious metabolites. It has been established that hypoperfusion or chronic oligemia could induce cortical atrophy through slow starvation of brain parenchyma [14
]. Intracranial atherosclerosis is a major cause of brain hypoperfusion and stroke. Furthermore, infarcts are present in approximately 40% of subjects with AD and the presence of infarcts has been shown to significantly increase the likelihood of dementia in subjects harboring both infarcts and AD histopathology [15
The reports by ourselves and others [1
] of increased intracranial AVD in AD indicate that stenosis of the arteries supplying the brain may be at least partially responsible for reduced cerebral perfusion in AD. Possible molecular mechanisms linking AD pathology and hypoperfusion include ischemia-induced alterations in Aβ precursor protein (APP) expression and APP cleavage [19
], both of which increase Aβ production. In addition, brain ischemia induces the production of hypoxia inducible factor that increases the production of β-secretase and increases Aβ levels [20
]. An even simpler hypothesis is that decreased cortical perfusion may reduce Aβ clearance from brain to the blood, analogous to the declining clearance of blood urea to urine with decreased renal perfusion seen, for example, in congestive heart failure.
It is evident that cardiovascular disease and AD are likely to have a synergistic effect on dementia [21
]. This statement is made with a strong caveat that although the statistical linkage between AD and intracranial AVD is significant, it is clear that AVD is not a precondition for the development of AD. The existence of cases of AD with very little AVD, and of very old NDC individuals with severe AVD, demonstrates that the association is not invariant.
Atherosclerotic vascular disease arises from the complex interactions of genetic and environmental factors [22
]. However, some of the complications of AVD are largely preventable by lifestyle modification and pharmacological manipulation [24
], suggesting therefore, AD may be at least partially preventable by similar methods. Furthermore, even if AD and AVD are only coincidentally related, about one-half of AD cases have significant contributory AVD that impairs cognition through ischemia/hypoxia and infarction in an additive fashion [15
]. On this basis alone, the systematic application of AVD prevention as a component of standard AD therapy should reduce functional impairment and decline in AD. If AVD is a synergistic or convergent disease with AD [21
], by accelerating disease onset and cognitive decline, then AVD therapy will have a correspondingly greater clinical impact in AD patients.
The clinical utility of a causal link between AD and AVD can only be definitively established by prospective clinical prevention trials using anti-atherosclerotic agents. Postmortem evaluation of the circle of Willis (CW) and major cerebral arteries seeks to establish the groundwork for such trials by revealing those AVD measures most strongly associated with the diagnosis of AD. In the present study, we compare the degree of CW atherosclerosis between AD and NDC individuals by rigorously measuring the index of occlusion in postmortem specimens. In addition, the functional repercussions of arterial stenosis on brain hemodynamics and hydrodynamics are discussed.