sTREM2 Mediates the Correlation Between BIN1 Gene Polymorphism and Tau Pathology in Alzheimer’s Disease

Article type: Research Article

Authors: Guo, Fan^{a; 1} | Tan, Meng-Shan^{a; b; c; 1; *} | Hu, Hao^{b; 1} | Ou, Ya-Nan^a | Zhang, Ming-Zhan^c | Sheng, Ze-Hu^a | Chi, Hao-Chen^a | Tan, Lan^{a; b; c; *} | Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [b] Department of Neurology, Qingdao Hospital, University of Health and Rehabilitation Sciences, Qingdao, China | [c] Department of Neurology, School of Clinical Medicine, Shandong Second Medical University, Weifang, China

Correspondence: [*] Correspondence to: Meng-Shan Tan, MD, PhD, and Lan Tan, MD, PhD, Department of Neurology, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China. Tel.: +86 532 8890 5659; Fax: +86 532 8890 5659; E-mail: tanmengshan@163.com (M.S.T.); E-mail: dr.tanlan@163.com (L.T.).

Note: [1] These authors contributed equally to this work.

Note: [2] Data used in preparation for 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 the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-ontent/uploads/how_to_apply/.

Abstract: Background:Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer’s disease (AD). Objective:To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods:Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer’s Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results:In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions:This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.

Keywords: Alzheimer’s disease, BIN1, microglia, polymorphism, sTREM2, tau pathology

DOI: 10.3233/JAD-240372

Journal: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 693-704, 2024