Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

Abstract

Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer's disease (AD) is causal remains unclear. The recent failures to demonstrate the efficacy of several amyloid beta-modifying drugs may indicate the possibility that the observed association is not causal. These failures also led to efforts to develop tau-directed treatments whose efficacy is still tentative. Herein, we conducted a two-sample Mendelian randomization analysis to determine whether the relationship between the cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and the risk of AD is causal. We used the summary statistics of a 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 the association between the change in the genetically predicted CSF biomarkers and LOAD risk.We found a modest decrease in the LOAD risk per one standard deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 0.63 for AD; 95% confidence interval[CI], 0.38-0.87; P = 0.02). In contrast, we observed a significant increase in the LOAD risk per one SD increase in the genetically predicted CSF p-tau (OR, 2.37; 95% CI, 1.46-3.28; P = 1.09×10 -5 ). However, no causal association was observed of the CSF t-tau with the LOAD risk (OR, 1.15; 95% CI, 0.85-1.45; P = 0.29). Our findings need to be validated in future studies with more genetic variants identified in larger GWASs for CSF biomarkers.Alzheimer's disease (AD), a leading cause of dementia, is the largest burden source of morbidity and mortality in older adults. One in every 85 individuals is expected to develop AD, which means that delaying the onset by one year can reduce the number of patients with AD worldwide up to 9 million by 2020 1 . Given that eightfold as many individuals have preclinical AD at risk of progression 2 , the development of disease-modifying therapies is urgently required. Amyloid beta (Aβ) peptides are transmembrane amyloid precursor proteins 3 and tau is a microtubule-associated protein 4 . Decades of research have accumulated the evidence on the pathophysiology of Aβ and tau proteins that independently form plaques and tangles and lead normal functional neurons into a disabled state, AD 5 . Understanding AD as the result of abnormal proteins, extracellular amyloid plaques, and intraneuronal neurofibrillary tau tangles, two-thirds of the novel treatment pipelines aim at diseasemodifying therapies, 90% of which are anti-amyloid and anti-tau protein agents 6 .However, numerous trials to develop novel therapies targeting the amyloid plaques to modify the disease progress recently turned out failures. These failures could bring a reasonable doubt about the role of Aβ in the pathophysiology of AD with delicate elaboration 7 . One possible explanation of the failure of clinical trials targeting the amyloid plaques is that the intervention is perfor...