Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer's disease

Abstract

We postulate that severe atherosclerotic occlusion of the circle of Willis and leptomeningeal arteries is an important factor in the pathogenesis of some sporadic Alzheimer's disease (AD) cases. These arterial stenoses are complicated by an overwhelming amyloid accumulation in the walls of leptomeningeal and cortical arteries resulting in a significant decrease in perfusion pressure and consequent ischemia/hypoxia of the brain tissue. We also propose that the distal areas of the white matter (WM) will be the first affected by a lack of oxygen and nutrients. Our hypotheses are supported by the following observations: (1) the number of stenoses is more frequent in AD than in the control population (p = 0.008); (2) the average index of occlusion is greater in AD than in the control group (p < 0.00001); (3) the index of stenosis and the total number of stenoses per case are positively correlated (R = 0.67); (4) the index of stenosis correlates with the neuropathological lesions of AD and with the MMSE psychometric test; (5) the number and degree of atherosclerosis of the anterior, middle and posterior cerebral arteries is more severe in cases of AD than in the control population; (6) atherosclerosis severity is apparently associated with the severity of the vascular amyloidosis; (7) the WM rarefaction correlates with the severity of the atherosclerosis and vascular amyloidosis; (8) the total cell count and microvessel count in the areas of WM rarefaction correlate with the neuropathological lesions of AD and with the MMSE score. Our data strongly suggest that severe hemodynamic disturbances contribute to sporadic AD and support the numerous observations indicating cardiovascular system participation in the pathogenesis of these dementias.

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

“…Cerebral blood supply is limited by the vascular narrowing caused by these lesions (Iadecola, 2003;Beach et al, 2007). Indeed, cerebral blood flow (CBF) is reduced in the early stages of AD and the reactivity of cerebral blood vessels is impaired (reviewed in Kalaria and Ballard, 1999;Matsuda, 2001;Kalback et al, 2004). Chronic brain hypoperfusion (CBH) is a pre-clinical condition of mild cognitive impairment (MCI), a condition thought to precede AD, and is an accurate indicator for predicting AD development de la Torre, 1999;Meyer et al, 2000;Maalikjy Akkawi et al, 2005;Ruitenberg et al, 2005).…”

P2‐107: Intracranial Atherosclerosis as a contributing factor to Alzheimer's disease Dementia

“…The reports by ourselves and others [1][2][3][4][5] 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 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][2][3][4][5].…”

Alzheimer's Factors in Ischemic Brain Injury

“…In this way a novel and more effective therapy approaches www.intechopen.com can be formulated and more data on different kind amyloidosis can be gathered. Aforementioned data suggest that reducing movement of -amyloid peptide from blood to brain tissue (Dickstein et al, 2006) and significantly improving reverse transport from brain into blood plasma ) and preventing ischemic events in neurons (Pluta 2007c see for references) are principal main future points in treatment of ischemic brain injury (Iwata et al, 2001;Moore, O'Banion 2002;Cheng et al, 2003;Deane et al, 2003;Borlongan et al, 2004;Deane et al, 2004a;Deane et al, 2004b;Guo et al, 2004;Kalback et al, 2004;Koistinaho et al, 2004;Tanzi et al, 2004;Pluta, Ulamek 2008]. Current data provide new information that injection with -amyloid peptide reduces blood-brain barrier leakage, amyloid burden and microgliosis in transgenic model of amyloid pathology (Dickstein et al, 2006).…”