Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
J Hum Genet. 2022 Aug;67(8):459-463. doi: 10.1038/s10038-022-01026-z. Epub 2022 Mar 7.
As a promising diagnostic and prognostic biomarker for Alzheimer's Disease (AD), plasma p-tau181 is robustly differentiated AD dementia from non-AD neurodegenerative diseases. We aimed to discover single nucleotide polymorphisms (SNPs) associated with plasma phosphorylated tau at threonine 181 (p-tau181) levels that affect the risk of developing AD. We carried out a genome-wide association study for plasma p-tau181 levels using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The thresholds of P < 5 × 10 was used for suggestive associations, and thresholds of P < 5 × 10 was used for significant associations. Subsequently, we tested whether the associations remained significant in subgroup analysis and examined the impact of SNPs on the longitudinal changes in plasma p-tau181 levels. A total of 714 eligible non-Hispanic white participants with plasma p-tau181 data were included. The most significant SNP (rs769449, P = 6.26 × 10) in APOE gene was suggestively associated with plasma p-tau181, which is close to the genome-wide significance threshold. The minor allele (A) of rs769449 in the APOE was associated with higher plasma p-tau181 levels in a dose-dependent fashion. Besides, rs769449- A carriers were more likely to exhibit a greater longitudinal cognitive decline (P = 0.03). Our results suggest that the AD risk variant in the APOE gene participates in the regulation of plasma p-tau181. The plasma p-tau181 concentration could be a useful endophenotype for identifying risk for AD in elderly individuals.
作为阿尔茨海默病（AD）有前途的诊断和预后生物标志物，血浆 p-tau181 可将 AD 痴呆与非 AD 神经退行性疾病明显区分开来。我们旨在发现与血浆磷酸化 tau 第 181 位苏氨酸（p-tau181）水平相关的单核苷酸多态性（SNP），这些 SNP 会影响 AD 的发病风险。我们使用阿尔茨海默病神经影像学倡议（ADNI）的参与者进行了血浆 p-tau181 水平的全基因组关联研究。使用 P < 5 × 10 作为提示关联的阈值，使用 P < 5 × 10 作为显著关联的阈值。随后，我们测试了这些关联在亚组分析中是否仍然显著，并检查了 SNP 对血浆 p-tau181 水平纵向变化的影响。共有 714 名符合条件的非西班牙裔白人参与者具有血浆 p-tau181 数据。APOE 基因中最显著的 SNP（rs769449，P = 6.26 × 10）提示与血浆 p-tau181 相关，接近全基因组显著阈值。APOE 中的 rs769449 次要等位基因（A）与血浆 p-tau181 水平呈剂量依赖性升高相关。此外，rs769449-A 携带者更有可能表现出更大的纵向认知下降（P = 0.03）。我们的结果表明，APOE 基因中的 AD 风险变异参与了血浆 p-tau181 的调节。血浆 p-tau181 浓度可能是识别老年人 AD 风险的有用内表型。
