Background There has been unprecedented progress in the development of blood-based biomarkers (BBMs such as p-tau217 to detect Alzheimer Disease (AD) pathology – characterised by the accumulation of Amyloid-Beta (Aβ) and hyper-phosphorylated tau (T). However, BBM performance in “real-world” memory clinic contexts remains unclear. Methods Using high-sensitivity immunoassays, plasma p-tau217 was assessed in 554 participants. Two cohorts were studied: (i) a memory clinic validation cohort of 108 older adults (69 ± 6.5 years; 54.6% female) with early cognitive symptoms and paired plasma/cerebrospinal fluid (CSF) at time of diagnostic Lumbar Puncture (LP) and (ii) a broader replication cohort of 446 individuals ranging from cognitively-unimpaired middle-aged adults to older adults with established AD with 18-month follow-up. Plasma P-tau217 performance was examined against clinically established CSF Aβ+/T+ cut-offs using Area-Under the Curve (AUC) analysis. Plasma cut-offs were optimised vs CSF based on maximal Youden index. Results In the memory clinic cohort, plasma p-tau217 exhibited excellent performance for the detection of Aβ pathology (AUC: 0.91, 0.86-0.97). Plasma p-tau217 was nearly 4-fold higher in Aβ+ (13.89; 7.36-19.0pg/mL) vs Aβ- (3.72; 2.80-4.09pg/mL, U = 230, p<0.001) participants. Plasma p-tau217 was superior in the identification of Aβ vs T pathology (p<0.05, DeLong Test) and outperformed p-tau181 and other BBMs(all p<0.05, DeLong Test). In the replication cohort, plasma p-tau217 maintained >90% accuracy for clinical AD and was significantly associated with clinically meaningful cognitive decline over 18 months (Odds Ratio 1.40; 1.06-1.85, p=0.02). In the initial memory clinic cohort, application of plasma p-tau217 as a diagnostic test would have reduced the need for LPs by over half (56.5%). Conclusion Plasma p-217 demonstrates excellent diagnostic and prognostic performance in older adults with AD, representing an amyloid-responsive measure which also predicts meaningful cognitive decline in established AD. Incorporation of plasma p-tau217 in memory clinic settings may substantially reduce the need for over half of diagnostic LPs.

中文翻译：

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血浆 P-tau217 作为老年人阿尔茨海默病的血液生物标志物表现出出色的诊断和预后性能


背景 用于检测阿尔茨海默病 (AD) 病理学的血液生物标记物（BBM，如 p-tau217）的开发取得了前所未有的进展，其特征是淀粉样蛋白 - β (Aβ) 和过度磷酸化 tau (T) 的积累。然而，BBM 在“现实世界”记忆诊所环境中的表现仍不清楚。方法使用高灵敏度免疫测定法，对 554 名参与者的血浆 p-tau217 进行了研究：(i) 108 名老年人的记忆诊所验证队列。 （69 ± 6.5 岁；54.6% 女性）在诊断性腰椎穿刺 (LP) 时出现早期认知症状和配对血浆/脑脊液 (CSF)，以及 (ii) 由 446 名个体组成的更广泛的复制队列，范围从认知未受损的中年到使用曲线下面积 (AUC) 分析，对照临床确定的 CSF Aβ+/T+ 临界值，对患有 AD 的老年人进行 18 个月随访的血浆 P-tau217 性能检查。与基于最大 Youden 指数的 CSF 进行优化。结果 在记忆诊所队列中，血浆 p-tau217 在检测 Aβ 病理学方面表现出优异的性能（AUC：0.91、0.86-0.97）。 Aβ+ (13.89; 7.36-19.0pg/mL) 参与者的血浆 p-tau217 比 Aβ- (3.72; 2.80-4.09pg/m​​L, U = 230, p<0.001) 参与者高出近 4 倍。血浆 p-tau217 在识别 Aβ 与 T 病理学方面表现更佳（p<0.05，DeLong 测试），并且优于 p-tau181 和其他 BBM（全部 p<0.05，DeLong 测试）。在复制队列中，血浆 p-tau217 对临床 AD 的准确性保持了 >90%，并且与 18 个月内有临床意义的认知能力下降显着相关（优势比 1.40；1.06-1.85，p=0.02）。 在最初的记忆诊所队列中，应用血浆 p-tau217 作为诊断测试将使对 LP 的需求减少一半以上 (56.5%)。结论 血浆 p-217 在患有 AD 的老年人中表现出优异的诊断和预后性能，代表了一种淀粉样蛋白反应性指标，也可以预测已确诊的 AD 中有意义的认知能力下降。在记忆诊所环境中加入血浆 p-tau217 可能会大大减少对一半以上诊断 LP 的需求。