Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R² ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R² ≤ 0.48) approached that of tau-PET (0.44 ≤ R² ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).

聚集的不溶性 tau 蛋白是阿尔茨海默病的两个定义特征之一。由于临床症状与 tau 聚集体密切相关，因此药物开发和临床诊断需要具有成本效益且易于获得的 tau 聚集体特异性液体生物标志物；然而，最近的研究表明，目前可用的液体生物标志物无法特异性追踪 tau 蛋白聚集体。我们证明含有残基 243 的 tau 微管结合区 (MTBR) (MTBR-tau243) 是一种新的脑脊液 (CSF) 生物标志物，特异性针对不溶性 tau 聚集体，并将其与多种其他磷酸化 tau 测量值 (p-tau181、 p-tau205、p-tau217 和 p-tau231）在两个独立队列中（BioFINDER-2， n = 448；和 Knight 阿尔茨海默病研究中心， n = 219）。 MTBR-tau243 与 tau 正电子发射断层扫描 (PET) 和认知的相关性最强，而与淀粉样蛋白 PET 的相关性最低。与 p-tau205 结合，MTBR-tau243 解释了 tau-PET 负担的大部分总方差 (0.58 ≤ R ² ≤ 0.75)，并且预测认知测量的表现 (0.34 ≤ R ² ≤ 0.48) 接近 tau-PET ( 0.44≤R ² ≤0.52)。与脑脊液 p-tau 物种不同，MTBR-tau243 水平随不溶性 tau 聚集体纵向增加。 CSF MTBR-tau243 是 tau 聚集病理学的特异性生物标志物，可用于介入试验和患者诊断。基于这些发现，我们建议修订 A/T/(N) 标准，将 MTBR-tau243 纳入代表不溶性 tau 聚集体 (“T”)。