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The complement cascade in Alzheimer’s disease: a systematic review and meta-analysis

Abstract

Genetic evidence implicates a causal role for the complement pathway in Alzheimer’s disease (AD). Since studies have shown inconsistent differences in cerebrospinal fluid (CSF) and peripheral blood complement protein concentrations between AD patients and healthy elderly, this study sought to summarize the clinical data. Original peer-reviewed articles measuring CSF and/or blood concentrations of complement or complement regulator protein concentrations in AD and healthy elderly control (HC) groups were included. Of 2966 records identified, means and standard deviations from 86 studies were summarized as standardized mean differences (SMD) by random effects meta-analyses. In CSF, concentrations of clusterin (NAD/NHC = 625/577, SMD = 0.53, Z8 = 8.81, p < 0.005; I2 < 0.005%) and complement component 3 (C3; NAD/NHC = 299/522, SMD = 0.45, Z3 = 3.21, p < 0.005; I2 = 68.40%) were significantly higher in AD, but differences in C1q, C-reactive protein (CRP), serum amyloid protein (SAP), and factor H concentrations were not significant. In peripheral blood, concentrations of CRP were elevated in AD (NAD/NHC = 3404/3332, SMD = 0.44, Z43 = 3.43, p < 0.005; I2 = 93.81%), but differences between groups in C3, C4, C1-inhibitor, SAP, factor H and clusterin concentrations were not significant, and inconsistent between studies. Of 64 complement pathway proteins or regulators in the quantitative synthesis, trends in C1q, factor B, C4a, and late-stage complement pathway components (e.g. C9) in blood, C4 in CSF, and the membrane attack complex in blood and CSF, might be investigated further. The results collectively support elevated complement pathway activity in AD, which was best characterized by increased CSF clusterin concentrations and less consistently by CSF C3 concentrations. Complement activity related to an AD diagnosis was not reflected consistently by the peripheral blood proteins investigated.

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Acknowledgements

We would like to thank Drs Bradley Hyman, Lora Dukic, Elizabeta Mukaetova-Ladinska, Tamas Fulop, Simon Lovestone, Abhaya Gupta, Giovanni Zuliani, Sarah Aldred, Carlo Patrono, Marco Crescenzi, Wolff Kirsch, Friedrich Leblhuber, Muhammet Cemal Kizilarslanoglu, Asija Zaciragic, Orhan Lepara, and Loic Dayon for their correspondences, and Shaolin Liang for her contribution to this work. Funding was provided by the Alzheimer’s Association (USA) and Brain Canada (AARG501466). SHK and WS acknowledge support from the Heart and Stroke Foundation Canadian Partnership for Stroke Recovery. SHK, CW, YZ, HM, ST, XH, and WS acknowledge support from the Department of Pharmacology & Toxicology, University of Toronto.

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Krance, S.H., Wu, CY., Zou, Y. et al. The complement cascade in Alzheimer’s disease: a systematic review and meta-analysis. Mol Psychiatry 26, 5532–5541 (2021). https://doi.org/10.1038/s41380-019-0536-8

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