Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer’s disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217WashU] and p-tau217WashU) as well as with immunoassays (p-tau217Lilly, p-tau217Janssen, p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the FDA-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff<0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff<0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff=0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared to immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff<0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff<0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff<0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff<0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff<0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff<0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R2 %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff<0.024). The main results were replicated in an external cohort from Washington University in St Louis (n =219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET, and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.

中文翻译：

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关键血浆磷酸化 tau 217 生物标志物检测的全面头对头比较


血浆磷酸化 tau 217 （p-tau217） 是目前最有前途的可靠检测阿尔茨海默病 （AD） 病理的生物标志物。已经开发了各种 p-tau217 测定，但它们的相对性能尚不清楚。我们使用淀粉样蛋白-β （Aβ）-PET 、 tau-PET 和认知的横断面和纵向测量比较了关键血浆 p-tau217 检测作为结局，并将它们与脑脊液 （CSF） 生物标志物检测进行了基准比较。分析了来自瑞典 BioFINDER-2 队列的 998 名个体 （平均 [范围] 年龄 68.5[20.0-92.5]，53% 为女性）的样本，包括认知未受损和认知受损的个体。使用质谱 （MS） 测定 （磷酸化和非磷酸化 [%p-tau217WashU] 和 p-tau217WashU 之间的比率） 以及免疫测定 （p-tau217Lilly、p-tau217Janssen、p-tau217ALZpath） 测量血浆 p-tau217。CSF 生物标志物包括 p-tau217Lilly、FDA 批准的 p-tau181/Aβ42Elecsys 和 p-tau181Elecsys。所有血浆 p-tau217 检测均表现出对异常 Aβ-PET （AUC 范围： 0.91-0.96） 和 tau-PET （AUC 范围： 0.94-0.97） 的高检测能力。血浆 %p-tau217WashU 性能最高，AUCs 显著高于所有免疫测定 （Pdiff<0.007）。对于检测 Aβ-PET 状态，%p-tau217WashU 的准确度为 0.93 （免疫测定：0.83-0.88），灵敏度为 91% （免疫测定：84-87%），特异性为 94% （免疫测定：85-89%）。在免疫测定中，p-tau217Lilly 和血浆 p-tau217ALZpath 的 Aβ-PET 状态 AUC 高于血浆 p-tau217Janssen （Pdiff<0.006），p-tau217Lilly 在 tau-PET 状态方面优于血浆 p-tau217ALZpath （Pdiff=0.025）。与免疫测定相比，血浆 %p-tau217WashU 与所有 PET 载量结局的相关性更强;基线 Aβ-PET 载量 （R2： 0.72;免疫测定：0.47-0.58;Pdiff<0.001）、基线 tau-PET 载量 （R2： 0.51;免疫测定： 0.38-0.45;Pdiff<0.001）、纵向 Aβ-PET 载量 （R2： 0.53;免疫测定： 0.31-0.38;Pdiff<0.001） 和纵向 tau-PET 载量 （R2： 0.50;免疫测定： 0.35-0.43;Pdiff<0.014）。在免疫测定中，血浆 p-tau217Lilly 与 Aβ-PET 载量的相关性高于血浆 p-tau217Janssen （Pdiff<0.020），与 tau-PET 载量的相关性高于血浆 p-tau217Janssen 和血浆 p-tau217ALZpath （均 Pdiff<0.010）。血浆 %p-tau217 与基线认知 （简易精神状态检查[MMSE]）的相关性也比所有免疫测定 （R2 %p-tau217WashU： 0.33;免疫测定： 0.27-0.30;Pdiff<0.024）。主要结果在圣路易斯华盛顿大学的外部队列中重复 （n =219）。最后，p-tau217NULISA 在两个队列的亚群中表现出与其他免疫测定相似的性能。总之，基于 MS 和免疫测定的 p-tau217 检测在识别 Aβ-PET、tau-PET 和认知异常方面通常表现良好，但 %p-tau217WashU 的表现明显优于所有检查的免疫测定。血浆 %p-tau217 可被视为 AD 病理学的独立确认试验，而一些免疫测定可能更适合作为分诊试验，其中阳性结果通过第二次检测确认，这需要通过未来纳入多个队列结果的综述来确定。