Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease

Thal, Dietmar Rudolf, Papassotiropoulos, Andreas, Saido, Takaomi C., Griffin, W. Sue T., Mrak, Robert E., Kolsch, Heike, Del Tredici, Kelly, Attems, Johannes and Ghebremedhin, Estifanos (2010) Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathologica, 120 2: 169-183. doi:10.1007/s00401-010-0707-9


Author Thal, Dietmar Rudolf
Papassotiropoulos, Andreas
Saido, Takaomi C.
Griffin, W. Sue T.
Mrak, Robert E.
Kolsch, Heike
Del Tredici, Kelly
Attems, Johannes
Ghebremedhin, Estifanos
Title Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease
Journal name Acta Neuropathologica   Check publisher's open access policy
ISSN 0001-6322
1432-0533
Publication date 2010-08
Sub-type Article (original research)
DOI 10.1007/s00401-010-0707-9
Volume 120
Issue 2
Start page 169
End page 183
Total pages 15
Place of publication Heidelberg, Germany
Publisher Springer
Collection year 2011
Language eng
Subject C1
920112 Neurodegenerative Disorders Related to Ageing
060110 Receptors and Membrane Biology
Abstract The deposition of amyloid β-protein (Aβ) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer’s disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Aβ-deposits. In addition, as in Alzheimer’s disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) ε4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Aβ-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Aβ-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE ε4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the α2macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE ε4-associated subtype of AD. © Springer
Keyword Alzheimer's disease
Cerebral amyloid angiopathy
Apolipoprotein E (APOE)
α2Macroglobulin receptor/low-density lipoprotein receptor-related protein (LRP-1)
EAAT-2
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Biomedical Sciences Publications
 
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Created: Sun, 11 Jul 2010, 00:10:00 EST