Impact of Serum Calcium Levels on Alzheimer’s Disease: A Mendelian Randomization Study

Article type: Research Article

Authors: He, Yating^a | Zhang, Haihua^b | Wang, Tao^{c; d} | Han, Zhifa^{e; f; g} | Ni, Qing-bin^h | Wang, Kun^h | Wang, Longcaiⁱ | Zhang, Yan^j | Hu, Yang^k | Jin, Shuilin^l | Sun, Bao-liang^m | Liu, Guiyou^{b; n; o; *}

Affiliations: [a] Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China | [b] Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China | [c] Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China | [d] Chinese Institute for Brain Research, Beijing, China | [e] School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China | [f] State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China | [g] Department of Pathophysiology, Peking Union Medical College, Beijing, China | [h] Postdoctoral Workstation, Taian City Central Hospital, Taian, Shandong, China | [i] Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, China | [j] Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, China | [k] School of Life Science and Technology, Harbin Institute of Technology, Harbin, China | [l] Department of Mathematics, Harbin Institute of Technology, Harbin, China | [m] Department of Neurology, The Second Affiliated Hospital; Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, China | [n] Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China | [o] National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, China

Correspondence: [*] Correspondence to: Guiyou Liu, Department of Neurology, Xuanwu Hospital, Capital Medical University, Room 1037, Donghuajinzuo, Guanganmennei Street, XiCheng District, Beijing 100053, China. E-mail: [email protected].

Abstract: Background:Altered calcium homeostasis is hypothesized to underlie Alzheimer’s disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. Objective:To develop effective therapies, we should establish the causal link between serum calcium levels and AD. Methods:Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. Results:IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35–0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. Conclusion:In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.

Keywords: Alzheimer’s disease, genome-wide association study, inverse-variance weighted, Mendelian randomization, serum calcium

DOI: 10.3233/JAD-191249

Journal: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 713-724, 2020