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Pathology of clinical and preclinical alzheimer's disease

Lookup NU author(s): Professor Johannes Attems


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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 b-protein (Ab) 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 Ab aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Ab aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD. © Springer-Verlag Berlin Heidelberg 2013.

Publication metadata

Author(s): Thal DR, Von Arnim C, Griffin WST, Yamaguchi H, Mrak RE, Attems J, Upadhaya AR

Publication type: Article

Publication status: Published

Journal: European Archives of Psychiatry and Clinical Neuroscience

Year: 2013

Volume: 263

Issue: Suppl. 2

Pages: 137-145

Print publication date: 01/11/2013

Online publication date: 28/09/2013

ISSN (print): 0940-1334

ISSN (electronic): 1433-8491

Publisher: Springer


DOI: 10.1007/s00406-013-0449-5

PubMed id: 24077890


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