Acta Neuropathologica

, Volume 120, Issue 2, pp 169–183 | Cite as

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

  • Dietmar Rudolf Thal
  • Andreas Papassotiropoulos
  • Takaomi C. Saido
  • W. Sue T. Griffin
  • Robert E. Mrak
  • Heike Kölsch
  • Kelly Del Tredici
  • Johannes Attems
  • Estifanos Ghebremedhin
Original Paper

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.

Keywords

Alzheimer’s disease Cerebral amyloid angiopathy Apolipoprotein E (APOEα2Macroglobulin receptor/low-density lipoprotein receptor-related protein (LRP-1EAAT-2 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Dietmar Rudolf Thal
    • 1
  • Andreas Papassotiropoulos
    • 2
  • Takaomi C. Saido
    • 3
  • W. Sue T. Griffin
    • 4
    • 5
  • Robert E. Mrak
    • 6
  • Heike Kölsch
    • 7
    • 12
  • Kelly Del Tredici
    • 8
  • Johannes Attems
    • 9
  • Estifanos Ghebremedhin
    • 1
    • 10
    • 11
  1. 1.Laboratory of Neuropathology, Institute of PathologyUniversity of UlmUlmGermany
  2. 2.Department of Molecular PsychologyUniversity of BaselBaselSwitzerland
  3. 3.Laboratory of Proteolytic NeuroscienceRIKEN Brain Science InstituteSaitamaJapan
  4. 4.Donald W. Reynolds Center on AgingUAMSLittle RockUSA
  5. 5.Geriatric Research Education and Clinical CenterVeteran’s Affairs Medical CenterLittle RockUSA
  6. 6.Department of PathologyUniversity of ToledoToledoUSA
  7. 7.Department of PsychiatryUniversity of BonnBonnGermany
  8. 8.Clinical Neuroanatomy (Department of Neurology), Center for Clinical ResearchUniversity of UlmUlmGermany
  9. 9.Institute for Ageing and HealthNewcastle UniversityNewcastle upon TyneUK
  10. 10.Institute for Clinical NeuroanatomyJ. W. Goethe UniversityFrankfurt am MainGermany
  11. 11.Department of Anatomy and Developmental Biology, School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  12. 12.IQWIGCologneGermany

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