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Apolipoprotein E allelotype is associated with neuropathological findings in Alzheimer's disease

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Abstract

In a consecutive hospital-based autopsy series, we examined the relationship between apolipoprotein E (apoE) and Alzheimer’s disease (AD) and investigated the clinicopathological relationship in AD. The study population included 99 patients (mean age 81 years) with AD-related neuropathological findings at death, of whom 83 were diagnosed with AD according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) classification, and a control group of patients without neurodegenerative disease (n = 1429). The patients were apoE genotyped and the density of β-amyloid senile plaques, neuritic plaques and neurofibrillary tangles was estimated in the cortex and hippocampus. The utility of immunohistochemical staining using an antibody directed against apoE4 in paraffin-embedded tissue was also evaluated. Among patients with “definite AD” according to CERAD, 65 % were ε4 carriers, compared to 32 % among controls (p < 0.001). The risk of ε4 carriers to develop AD was higher (odds ratio = 4.65, p = 0.001) than for non-ε4 carriers. The amount of β-amyloid deposition and neurofibrillary pathology differed significantly (p < 0.01) between the genotypes, with increasing densities from ε2 carriers to homozygous ε4 carriers. The effect of ε4 on the presence of clinical symptoms was attenuated and non-significant after adjusting for AD-related neuropathological findings. There was an association between these findings and the presence of clinical symptoms of AD, with neurofibrillary tangles separating patients with and without symptoms of AD markedly better than β-amyloid. In addition, we found a strong relationship between genotype and immunohistochemical apoE4-staining intensity. In conclusion, this Scandinavian autopsy study shows that the apoE polymorphism is associated with the probability of AD and influences the deposition of β-amyloid and neurofibrillary pathology. Our findings suggest that the association between apoE and clinical manifestations of AD is mediated mainly through the neuropathological features of AD. Further, we found a relationship between AD-related findings and clinical symptoms of AD with neurofibrillary tangles associating most strongly with clinical symptoms. Finally, immunohistochemical staining in brain specimens is useful for determining ε4- or non-ε4-carrier status.

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Acknowledgments

This work was supported by the Department of Pathology, Oslo University Hospital, Oslo, Norway, and the Research Council of Norway (Norges forskningsråd). We also wish to thank S. H. Brorson, Oslo University Hospital, Oslo, Norway, and I. L. Goverud for their excellent technical support.

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  1. Department of Pathology, Oslo University Hospital-Ullevål, P.O. Box 4956, Nydalen, 0424, Oslo, Norway

    Neena Theresa Kumar, Else Marit Løberg & Jan Mæhlen

  2. Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway

    Knut Liestøl

  3. Oslo University hospital-Rikshospitalet, Oslo, Norway

    Henrik Mikael Reims

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Kumar, N.T., Liestøl, K., Løberg, E.M. et al. Apolipoprotein E allelotype is associated with neuropathological findings in Alzheimer's disease. Virchows Arch 467, 225–235 (2015). https://doi.org/10.1007/s00428-015-1772-1

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