Intracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia

Abstract

Background: A substantial body of evidence collected from epidemiologic, correlative, and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions used to maintain vascular health and function as a component of standard AD therapy offers the prospect of mitigating the presently inexorable course of dementia. To assess this hypothesis, it is vital to rigorously establish the measures of AVD that are most strongly associated with an AD diagnosis.

Methods: A precise neuropathological diagnosis was established for all subjects, using a battery of genetic, clinical, and histological methods. The severity of atherosclerosis in the circle of Willis was quantified by direct digitized measurement of arterial occlusion in postmortem specimens and was compared between AD and nondemented control groups by calculating a corresponding index of occlusion.

Results: Atherosclerotic occlusion of the circle of Willis arteries was more extensive in the AD group than in the nondemented control group. Statistically significant differences were also observed between control and AD groups with regard to Braak stage, total plaque score, total neurofibrillary tangle score, total white matter rarefaction score, brain weight, Mini-Mental State Examination scores, and apolipoprotein E allelic frequencies.

Conclusions: Our results, combined with a consideration of the multifaceted effects of impaired cerebral circulation, suggest an immediate need for prospective clinical trials to assess the efficacy of AD prevention using antiatherosclerotic agents.

Figure 1

Representative cross-sections of the circle of Willis arteries. The top panel (A) illustrates a series of arterial sections in which the lumenal area is minimally reduced. The inset indicates the external area (red) and luminal area (blue) that were manually encircled. The area was calculated automatically with ImagePro Express, v 4.0 software and an index of occlusion is derived from these numbers. The bottom panel (B) shows arteries with severe atherosclerosis. In some cases the arteries are almost occluded by the atheroma plaque.

Figure 2

A) The y-axis represents of the percentage of all arterial measurements taken. The index of occlusion, separated in deciles, is along the x-axis. The index of occlusion was also higher in the individual arteries of AD subjects compared to NDC subjects when separating by the percentage of measurements ≥ 60% (B), 70% (C) and 80% (D) index of occlusion. NDC, non-demented control; AD, Alzheimer's disease; VA, vertebral arteries; BA, basilar artery; PCA, posterior cerebral arteries; MCA, middle cerebral arteries; ICA, intracranial arteries; ACA, anterior cerebral arteries; * p<.05; **p<.01; ***p<.001.