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

Abstract

Background: Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. Recent failures to demonstrate the efficacy of several Aβ-modifying drugs may indicate a possibility that the observed association is not causal, which led to efforts to develop tau-directed treatments whose efficacy remains tentative. Methods: Herein, we conducted a two-sample Mendelian randomisation analysis to investigate shared genetic background between cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and risk for AD, and to find genetic evidence for causal association between these CSF biomarkers and risk for AD. We used summary statistics of genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively-normal controls. We tested association between changes in the genetically-predicted CSF biomarkers and LOAD risk. Results: We found a decrease in the 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 the LOAD risk per one-SD increase in the genetically-predicted CSF p-tau (OR, 19.46; 95% CI, 1.50–2.52×10 2 ; p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57–7.29×10 2 ; p = 0.02). Conclusions: Our findings suggest a shared genetic background between the CSF biomarkers and LOAD risk. Although it requires validation by future studies including more genetic variants identified in large-scale GWASs for CSF biomarkers, our results suggest a causal association between CSF biomarkers and risk for LOAD.