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Pathology of clinical and preclinical Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is characterized neuropathologically by the presence of amyloid plaques, neuritic plaques, and neurofibrillary tangles (NFTs). These lesions occur not only in demented individuals with AD but also in non-demented persons. In non-demented individuals, amyloid and neuritic plaques are usually accompanied with NFTs and are considered to represent asymptomatic or preclinical AD (pre-AD) pathology. Here, we defined and characterized neuropathological differences between clinical AD, non-demented pre-AD, and non-AD control cases. Our results show that clinical AD may be defined as cases exhibiting late stages of NFT, amyloid, and neuritic plaque pathology. This is in contrast to the neuropathological changes characteristic of pre-AD, which display early stages of these lesions. Both AD and pre-AD cases often exhibit cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD), and when they do, these AD-related pathologies were at early stages in pre-AD cases and at late stages in symptomatic AD. Importantly, NFTs, GVD, and CAA were also observed in non-AD cases, i.e., in cases without amyloid plaque pathology. Moreover, soluble and dispersible, high-molecular-weight amyloid β-protein (Aβ) aggregates detected by blue-native polyacrylamide gel electrophoresis were elevated in clinical AD compared to that in pre-AD and non-AD cases. Detection of NFTs, GVD, and CAA in cases without amyloid plaques, presently classified as non-AD, is consistent with the idea that NFTs, GVD, and CAA may precede amyloid plaque pathology and may represent a pre-amyloid plaque stage of pre-AD not yet considered in the current recommendations for the neuropathological diagnosis of AD. Our finding of early stages of AD-related NFT, amyloid, and GVD pathology provides a more clear definition of pre-AD cases that is in contrast to the changes in clinical AD, which is characterized by late stages of these AD-related pathologies. The observed elevation of soluble/dispersible Aβ aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Aβ aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD.

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Acknowledgments

The authors thank Mrs. Irina Kosterin, Mrs. Monika Riede, and Mrs. Kathrin Pruy for technical help, Dr. Kelly Del Tredici for reading and editing the manuscript and Prof. Dr. Heiko Braak for providing autopsy brains for this study. This study was supported by DFG grants TH624/4-1, TH624/6-1, and Alzheimer Forschung Initiative Grant #10,810 (DRT). Part of this study (JA) was supported by the Dunhill Medical Trust (R173/1110). Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research, UK.

Conflict of interest

DRT received a consultant honorarium from Simon-Kucher and Partners (Germany), and GE Healthcare (UK) and collaborated with Novartis Pharma Basel (Switzerland). CAFvA received honoraria for serving on the scientific advisory board of Nutricia GmbH and has received funding for travel and speaker honoraria from Sanofi-Aventis, Novartis, Pfizer, Eisai, and Nutricia GmbH, and has received research support from Heel GmbH.

This article is part of the supplement “Bridging the gap between Neurobiology and Psychosocial Medicine.” This supplement was not sponsored by outside commercial interests. It was funded by the German Association for Psychiatry and Psychotherapy (DGPPN).

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Authors and Affiliations

  1. Institute of Pathology - Laboratory of Neuropathology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, Ulm, Germany

    Dietmar Rudolf Thal & Ajeet Rijal Upadhaya

  2. Department of Neurology, University of Ulm, Ulm, Germany

    Christine von Arnim

  3. Donald W. Reynolds Center on Aging, UAMS, Little Rock, AR, USA

    W. Sue T. Griffin

  4. Geriatric Research Education and Clinical Center, Veteran’s Affairs Medical Center, Little Rock, AR, USA

    W. Sue T. Griffin

  5. Gunma University School of Health Sciences, Maebashi, Gunma, Japan

    Haruyasu Yamaguchi

  6. Department of Pathology, University of Toledo, Toledo, OH, USA

    Robert E. Mrak

  7. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    Johannes Attems

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  1. Dietmar Rudolf Thal
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Correspondence to Dietmar Rudolf Thal.

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Thal, D.R., von Arnim, C., Griffin, W.S.T. et al. Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 263 (Suppl 2), 137–145 (2013). https://doi.org/10.1007/s00406-013-0449-5

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