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

• Published in: Neuropathology and applied neurobiology Vol. 31; no. 6; pp. 589 - 599
• Main Authors: Tanskanen, M., Lindsberg, P. J., Tienari, P. J., Polvikoski, T., Sulkava, R., Verkkoniemi, A., Rastas, S., Paetau, A., Kiuru-Enari, S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2005; Blackwell Science
• Subjects: Aged, 80 and over; Amyloid beta-Peptides - metabolism; amyloid β-protein; apolipoprotein E genotype; Apolipoprotein E4; Apolipoproteins E - genetics; Biological and medical sciences; cerebral amyloid angiopathy; Cerebral Amyloid Angiopathy - genetics; Cerebral Amyloid Angiopathy - immunology; Cerebral Amyloid Angiopathy - pathology; complement; Complement Activation - immunology; Complement C3d - immunology; Complement C3d - metabolism; Complement C9 - immunology; Complement C9 - metabolism; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; dementia; Dementia - genetics; Dementia - immunology; Dementia - pathology; Female; Genotype; Human mycoses; Humans; Infectious diseases; Leukocytes - pathology; Male; Medical sciences; Mycoses; Mycoses of the nervous system; Nervous system (semeiology, syndromes); Neurology; Nervous system diseases; Cerebral amyloid angiopathy; apolipoprotein E genotype; Apolipoprotein E; β Amyloid protein; amyloid β-protein; Genotype; Activation; Complement; Dementia
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/j.1365-2990.2005.00652.x

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.