Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype.
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.
Tanskanen
M
M
Department of Pathology, University of Helsinki, Helsinki University Central Hospital, Finland. maarit.tanskanen@helsinki.fi
Lindsberg
P J
PJ
Tienari
P J
PJ
Polvikoski
T
T
Sulkava
R
R
Verkkoniemi
A
A
Rastas
S
S
Paetau
A
A
Kiuru-Enari
S
S
D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000276:immunology*; D015933:Complement C3d / Q000276:immunology / Q000378:metabolism; D003186:Complement C9 / Q000276:immunology / Q000378:metabolism; D003704:Dementia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D008297:Male
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D003186:Complement C9; D015933:Complement C3d