Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

Article type: Research Article

Authors: Kim, Soyeon^{a; 1} | Kim, Kiwon^{b; 1} | Nho, Kwangsik^{c; *} | Myung, Woojae^{d; *} | Won, Hong-Hee^{a; *}

Affiliations: [a] Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea | [b] Department of Psychiatry, Veteran Health Service Medical Center, Seoul, South Korea | [c] Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea

Correspondence: [*] Correspondence to: Hong-Hee Won, PhD, Samsung Adv-anced Institute of Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea. Tel.: +82 2 2148 7566; Fax: +82 2 3410 0534; E-mail: wonhh@skku.edu; Kwangsik Nho, PhD, Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA. Tel.: +1 317 963 7503; Fax: +1 317 963 7547; E-mail: knho@iupui.edu; Woojae Myung, MD, PhD, Department of Neuropsychiatry, Seoul National University Bundang Hospital 29, Gumi-ro 173beon-gil Bundang-gu, Seongnam-si, Gyeonggi-do 13619, South Korea. Tel.: +82 31 787 7430; Fax: +82 31 787 4058; E-mail: wjmyung@snubh.org.

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

Abstract: Background:Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer’s disease (LOAD) is causal remains unclear. Objective:We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. Methods:We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ1–42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. Results:We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87×10–3 for AD; 95%confidence interval [CI], 1.54×10–4–0.05; p = 8.91×10–5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50–2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57–7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). Conclusion:We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, tau

DOI: 10.3233/JAD-200671

Journal: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1197-1207, 2021