Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer’s disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain. NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline. We demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R2), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (βstd = 0.16) and impaired (βstd = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2 = 0.20). Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal.

中文翻译：

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含有 tau 片段的血浆 N 端（NTA-tau）：阿尔茨海默病中 tau 沉积的生物标志物

新型磷酸化 tau (p-tau) 血液生物标志物（例如 p-tau181、p-tau217 或 p-tau231）对阿尔茨海默病 (AD) 具有高度特异性，并且可以追踪淀粉样蛋白 -β (Aβ) 和 tau 病理学。然而，由于这些生物标志物与 Aβ 病理学的出现密切相关，因此很难确定不溶性 tau 聚集体对血液中血浆 p-tau 信号的贡献。因此，仍然需要一种能够特异性追踪大脑中不溶性 tau 积累的生物标志物。 NTA 是一种新型超灵敏检测方法，针对脑脊液 (CSF) 和血浆中含有 N 末端的 tau 片段 (NTA-tau)，该片段在 AD 中升高。使用两个特征良好的研究队列（BioFINDER-2，n = 1,294 和 BioFINDER-1，n = 932），我们研究了血浆 NTA-tau 水平与 AD 疾病进展之间的关联，包括 tau 积累、脑萎缩和认知障碍衰退。我们证明血浆 NTA-tau 在整个 AD 连续体中增加，尤其是在晚期，并且在 Aβ 阳性参与者中与 tau-PET 表现出中度至强的相关性（β = 0.54，p < 0.001），而与 Aβ 的相关性较弱-PET（β = 0.28，p < 0.001）。与血浆 p-tau181、GFAP、NfL 和 t-tau 不同，tau-PET 确定的 tau 病理学是 NTA-tau 方差的最显着贡献者（总 R2 的 52.5%），而 CSF 测量的 Aβ 病理学的贡献非常低Aβ42/40 (4.3%)。高基线 NTA-tau 水平可预测 AD 连续体参与者的 tau-PET 积累 (R2 = 0.27)、更严重的萎缩 (R2 ≥ 0.18) 和更严重的认知能力下降 (R2 ≥ 0.27)。与 Aβ 阴性对照相比，基线时认知未受损 (βstd = 0.16) 和认知受损 (βstd = 0.18) 的 Aβ 阳性患者的血浆 NTA-tau 水平随时间显着增加。最后，血浆 NTA-tau 水平的纵向增加与皮质厚度 (R2 = 0.21) 和认知 (R2 = 0.20) 的纵向急剧下降相关。我们的结果表明，血浆 NTA-tau 水平在整个 AD 连续体中增加，尤其是在 AD 中晚期阶段，并且与 AD 体内 tau 缠结沉积及其下游效应密切相关。此外，这种新型生物标志物有潜力成为一种经济有效且易于使用的工具，用于监测临床环境中的疾病进展和认知能力下降，并作为临床试验中的结果衡量标准，临床试验还需要评估成功去除 Aβ 的下游影响。