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

초록

Background: Whether the epidemiological association of amyloid-beta (A beta) 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 A beta 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 (A beta(1-42) [A beta], 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 A beta (odds ratio [OR], 2.87x10(-3) for AD; 95% confidence interval [CI], 1.54x10(-4)-0.05; p = 8.91x10(-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, 1.50-2.52x10(2); p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57-7.29x10(2); 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 A beta and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.

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