Mendelian Randomization Reveals Unidirectional Links Between Amyloid-β and Tau in Alzheimer's Disease.

Background and Purpose: Prior research has indicated that changes in the amyloid-beta (Aβ) biomarker precede tau biomarker alterations in Alzheimer's disease (AD). However, establishing causality through temporal correlations remains contentious. This study aimed to explore the causal relationship between Aβ and tau using Mendelian randomization (MR) analysis. Methods: We conducted two-sample MR analyses employing genome-wide association studies (GWASs) summary statistics for Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau (CSF pTau). Additionally, to reinforce and validate the results of the two-sample MR, we performed two-sample MR using tau PET GWAS summary statistics and one-sample MR analysis using autopsy data. In the one-sample MR analysis, the exposure and outcome variables were neuritic plaque burden and neurofibrillary tangle burden, respectively, determined through neuropathological examination. Results: The two-sample MR analysis unveiled a causal association between Aβ accumulation and CSF pTau level (BETA [standard error]=0.30 [0.10], p=0.004). The absence of heterogeneity and horizontal pleiotropy was confirmed. In contrast, there was no evidence causally relating CSF pTau level to Aβ accumulation (p=0.56). Our results were reinforced by consistently directional effects observed in the two-sample MR using tau PET GWAS and one-sample MR analysis, indicating a causal direction from Aβ burdens (measured by neuritic plaques) to tau burdens (measured by neurofibrillary tangles) (p=1.24×10-13). Conclusions: Our findings suggest a causal relationship between Aβ burdens and tau burdens in AD, reinforcing the notion of Aβ as a pivotal upstream factor in AD pathogenesis.