Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles

Abstract

The role of intracranial atherosclerosis in Alzheimer's disease (AD) has been a subject of debate since the first decade of the last century. The initial "vascular hypothesis" of AD was rejected after a series of mid-twentieth century gross anatomical postmortem studies that showed an inconstant relationship between intracranial atherosclerosis and senile dementia. These early studies did not utilize statistical methods, however, and the investigators did not appear to consider the possibility that intracranial atherosclerosis might have a probabilistic, rather than an absolute, effect on AD risk. Recent studies by three independent groups have found a significant statistical association between postmortem measures of circle of Willis atherosclerosis and AD. The present study was undertaken to further address the validity of this association in a large autopsy series, including cases diagnosed neuropathologically with vascular dementia (VaD) and non-AD dementias. Postmortem gross anatomical grading of circle of Willis atherosclerosis was performed in 397 subjects classified by neuropathological diagnosis, including 92 non-demented elderly controls, 215 with AD, 30 with VaD and 60 with non-AD dementias. Circle of Willis atherosclerosis was more severe in subjects with AD and VaD than in control subjects, while it was equivalent between control subjects and subjects with non-AD dementias. Increasing atherosclerotic grade increased the odds ratios (OR) for the diagnoses of both AD and VaD and also increased the ORs for both increased neuritic plaque density and higher Braak neurofibrillary tangle stage. The significance of these associations was retained after consideration of the effects of age, gender and the apolipoprotein E-epsilon4 allele. The results suggest that the statistical association between intracranial atherosclerosis and AD is not an artifact of diagnostic misclassification or of unequal distribution of the apolipoprotein E-epsilon4 allele.

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

“…When considering the entire population under study, the mean index of occlusion ranged from 33% (lowest) to 84% (highest); there would thus be a 51-unit or 306% (three-fold) increase in likelihood of AD from the lowest to the highest levels of stenosis. This number is similar to the odds ratios from carrying one ApoE ε4 allele and agrees with our previous observations using semi-quantitative atherosclerotic scoring on a much larger sample [1]. This association was also significant for specific CW arteries: BA, ICA, MCA, and PCA.…”

“…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].…”

Shared genetic contribution to ischemic stroke and Alzheimer's disease

“…The predominant cerebral vascular pathologies in IS are large vessel atherosclerosis (large vessel disease; LVD)15, 16 and small vessel arteriosclerosis (small vessel disease; SVD) 17. Both pathologies have been associated with AD.…”

Twenty-five years of the amyloid hypothesis of alzheimer disease: advances, failures and new perspectives

“…В ряде исследований показана связь между альцгеймеровскими изменениями и атеро-склерозом крупных экстра-и интракраниальных артерий [17][18][19], но не патологией мелких сосудов [20][21][22]. Тем не менее проспективно было показа-но, что прирост количества амилоидных бляшек связан с уменьшением эластичности сосудистой стенки и ареактивностью сосудов [23].…”