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Effect of CR1 Genetic Variants on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts

Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The complement component (3b/4b) receptor 1 gene (CR1) is considered as one of the most important genetic susceptibility loci in Alzheimer’s disease (AD). However, to date, few studies were performed to discover the possible effect of CR1 genetic variants on AD pathology in the brain. Here, we evaluated the potential role of CR1 common variants in AD-related pathology by assessing neuroimaging biomarkers and cerebrospinal fluid (CSF) proteins. Finally, a total of 812 subjects from the Alzheimer’s disease Neuroimaging Initiative database and eight single nucleotide polymorphisms (SNPs) after quality control procedures are enrolled in our analysis. After applied to multiple linear regression models, significant associations were proved to exist between rs4844609 and amyloid deposition in cingulated, frontal, parietal, and temporal on florbetapir 18F amyloid positron emission tomography. In the analysis of the impacts of CR1 genetic variants on brain structures, three SNPs (rs12034383, rs3737002, and rs6691117) were significantly linked to the changes in volume of middle temporal. In addition, rs10779339 showed a negative connection with the cerebral metabolism rate of glucose in the right temporal on 18F-fluorodeoxyglucose PET imaging. However, no significant statistical findings were detected between CR1 genetic variants and CSF proteins (amyloid β, total-tau, and p-tau) at baseline diagnose or in the follow-up study of 2 years. The results of our study indicated that CR1 plays a vital role in AD pathology mainly by influencing Aβ deposition, brain structure, and glucose metabolism during AD progression.

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Acknowledgments

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc., Biogen Idec Inc., Bristol-Myers Squibb Company, Eisai Inc., Elan Pharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare,; IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson & Johnson Pharmaceutical Research & Development LLC., Medpace, Inc., Merck & Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier; Synarc Inc., and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuroimaging at the University of Southern California.

This work was also supported by grants from the National Natural Science Foundation of China (81471309, 81171209, 81371406, 81501103, 81571245), the Shandong Provincial Outstanding Medical Academic Professional Program, Qingdao Key Health Discipline Development Fund, Qingdao Outstanding Health Professional Development Fund, and Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, and the Innovation Project for Postgraduates of Jiangsu Province (KYLX15_0958).

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Correspondence to Lan Tan or Jin-Tai Yu.

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The authors declare that they have no competing interests.

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Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:

http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Xi-Chen Zhu and Hui-Fu Wang contributed equally to this work.

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Zhu, XC., Wang, HF., Jiang, T. et al. Effect of CR1 Genetic Variants on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts. Mol Neurobiol 54, 551–562 (2017). https://doi.org/10.1007/s12035-015-9638-8

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