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

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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-ε4 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-ε4 allele.

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Acknowledgments

This research was supported by grants from the National Institute of Health to Dr. A. Roher (RO1 AG19795), to Dr. T. Beach (R01 NS38674) and to the Arizona Alzheimer’s Disease Core Center (P30 AG19610-01), and also by the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Consortium) and the Arizona Biomedical Research Commission (contract 0011, Arizona Parkinson’s Disease Center).

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  1. W.H. Civin Laboratory for Neuropathology, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ, 85351, USA

    Thomas G. Beach, Lucia I. Sue, Amanda Newell, Marissa Poston, Raquel Cisneros & Yoga Pandya

  2. School of Health Management and Policy, Arizona State University, Tempe, AZ, 85287, USA

    Jeffrey R. Wilson

  3. Napolean Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ, 85351, USA

    Chera Esh & Alex E. Roher

  4. Cleo Roberts Center for Clinical Research, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ, 85351, USA

    Donald J. Connor & Marwan Sabbagh

  5. Laboratory of Neuroinflammation, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ, 85351, USA

    Douglas G. Walker

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  1. Thomas G. Beach
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Beach, T.G., Wilson, J.R., Sue, L.I. et al. Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles. Acta Neuropathol 113, 13–21 (2007). https://doi.org/10.1007/s00401-006-0136-y

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