Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer’s Disease Risk by Altering Neuronal Degeneration

Article type: Research Article

Authors: Wang, Hui-Fu^a | Wan, Yu^b | Hao, Xiao-Ke^c | Cao, Lei^a | Zhu, Xi-Chen^a | Jiang, Teng^d | Tan, Meng-Shan^b | Tan, Lin^e | Zhang, Dao-Qiang^c | Tan, Lan^{a; b; e; *} | Yu, Jin-Tai^{a; b; *} | Disease Neuroimaging Initiative Alzheimer’s¹

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China | [b] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China | [c] Department of Computer Science and Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China | [d] Department of Neurology, Nanjing First Hospital, Nanjing Medical University, China | [e] Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China

Correspondence: [*] Correspondence to: Lan Tan, Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China. E-mail: [email protected] and Jin-Tai Yu, Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, China. Tel.: +1 415 988 0162; Fax: +1 415 476 0679; E-mails: [email protected] or [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://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

Abstract: Background: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer’s disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed. Objective: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis. Methods: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects. Results: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc = 0.047, rs13031703: pc = 0.042) and P-tau (rs744373: pc = 0.044, rs13031703: pc = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc = 0.011), CA1 (rs1469980: pc = 0.029) and parahippocampus (rs72838284, pc = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals. Conclusion: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.

Keywords: Aβ deposition, Alzheimer’s disease, BIN1, brain structure, cerebrospinal fluid, glucose metabolism

DOI: 10.3233/JAD-150972

Journal: Journal of Alzheimer's Disease, vol. 52, no. 1, pp. 179-190, 2016