Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
Department of Psychiatry, Veteran Health Service Medical Center, Seoul, South Korea.
J Alzheimers Dis. 2021;80(3):1197-1207. doi: 10.3233/JAD-200671.
Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer's disease (LOAD) is causal remains unclear.
We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD.
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.
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).
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.
淀粉样蛋白-β（Aβ）和 tau 病理学与晚发性阿尔茨海默病（LOAD）之间的流行病学关联是否具有因果关系尚不清楚。
本研究旨在探讨脑脊液（CSF）Aβ 和 tau 病理生物标志物的遗传背景与 LOAD 风险之间的关系。
我们进行了两样本 Mendelian 随机分析（MR）。我们使用了 3146 名个体的 CSF 生物标志物（Aβ1-42 [Aβ]、磷酸化 tau181 [p-tau]和总 tau [t-tau]）的全基因组关联研究汇总统计数据和 21982 例病例和 41944 例对照的 LOAD 数据。我们检测了遗传预测 CSF 生物标志物变化与 LOAD 风险之间的相关性。
我们发现，每增加一个标准差（SD）的遗传预测 CSF Aβ，LOAD 风险降低（优势比 [OR]，AD 为 2.87×10-3；95%置信区间 [CI]，1.54×10-4-0.05；p = 8.91×10-5）。相反，我们发现，遗传预测 CSF p-tau（OR，19.46；95%CI，1.50-2.52×102；p = 0.02）和 t-tau（OR，33.80；95%CI，1.57-7.29×102；p = 0.02）每增加一个 SD，LOAD 风险均增加。然而，仅在排除 APOE 变体（rs769449）后，p-tau 与 LOAD 风险之间的关联仍然显著。
我们发现 CSF 生物标志物与 LOAD 风险之间存在因果关系。我们的研究结果表明，LOAD 的病因涉及多种生物学过程，包括 Aβ 和 tau 蛋白途径。需要使用多个候选生物标志物的大规模数据进行进一步的 MR 研究，以阐明 LOAD 的病理生理学。
