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

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Abstract
There is growing evidence that in Alzheimer's disease (AD) amyloid β‐protein (Aβ) triggers a chronic inflammatory reaction in cerebral amyloid plaques, including complement proteins. Aβ 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 Aβ 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 ɛ4 (P = 0.0005) and overrepresentation of ɛ4 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 ɛ4+ (P = 0.02) and ɛ4 – (P = 0.06) subjects. Our study shows that complement proteins are deposited in the affected vessels in Aβ– associated CAA. They may solely represent the cerebral Aβ– burden associated to inflammatory stimuli, or signal a contribution in the clearance of cerebral Aβ, thereby contributing to the events associated with evolution of clinical dementia. Our results demonstrate a strong association between CAA and ApoE ɛ4 as well as dementia and suggest that the contribution of CAA to dementia is largely independent of ApoE ɛ4.