Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype

Neuropathol Appl Neurobiol. 2005 Dec;31(6):589-99. doi: 10.1111/j.1365-2990.2005.00652.x.


There is growing evidence that in Alzheimer's disease (AD) amyloid beta-protein (Abeta) triggers a chronic inflammatory reaction in cerebral amyloid plaques, including complement proteins. Abeta also accumulates cerebrovascularly in age- and AD-associated cerebral amyloid angiopathy (CAA). We investigated complement proteins in CAA in a population-based series using histological and immunohistochemical staining methods. The 74 subjects, aged 95 years or more, had undergone clinical neurological examination and apolipoprotein E (ApoE) genotyping. The brains had been studied for AD post-mortem, allowing us to relate the histopathological findings to clinical and genetic conditions. CAA with congophilic amyloid was found in 36/74 individuals (48.6%). The vascular amyloid deposits immunoreacted with antibodies to Abeta and complements 3d (C3d) and 9 (C9). The positivity in complement stains increased with growing severity of CAA (P = 0.001). The presence of CAA associated with ApoE epsilon4 (P = 0.0005) and overrepresentation of epsilon4 among those with moderate or severe vs. mild CAA (P = 0.03) was demonstrated. The presence of CAA associated with dementia (P = 0.01), which was contributed by both epsilon4+ (P = 0.02) and epsilon4- (P = 0.06) subjects. Our study shows that complement proteins are deposited in the affected vessels in Abeta-associated CAA. They may solely represent the cerebral Abeta- burden associated to inflammatory stimuli, or signal a contribution in the clearance of cerebral Abeta, thereby contributing to the events associated with evolution of clinical dementia. Our results demonstrate a strong association between CAA and ApoE epsilon4 as well as dementia and suggest that the contribution of CAA to dementia is largely independent of ApoE epsilon4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Amyloid beta-Peptides / metabolism
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Cerebral Amyloid Angiopathy / genetics*
  • Cerebral Amyloid Angiopathy / immunology*
  • Cerebral Amyloid Angiopathy / pathology
  • Complement Activation / immunology*
  • Complement C3d / immunology
  • Complement C3d / metabolism
  • Complement C9 / immunology
  • Complement C9 / metabolism
  • Dementia / genetics
  • Dementia / immunology
  • Dementia / pathology
  • Female
  • Genotype
  • Humans
  • Leukocytes / pathology
  • Male


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Apolipoproteins E
  • Complement C9
  • Complement C3d