Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

开发基于 tau 的阿尔茨海默病疗法需要了解 tau 疾病相关变化的时间。我们量化了显性遗传性阿尔茨海默病四个十年的疾病进展过程中脑脊液标志物中 tau 蛋白多个位点的磷酸化状态。我们确定了一种 tau 分期模式，其中位点特异性磷酸化变化发生在疾病进展的不同时期，并随着时间的推移遵循不同的轨迹。这些 tau 磷酸化状态变化与疾病的结构、代谢、神经退行性和临床标志物独特相关，一些（p-tau217 和 p-tau181）早在 20 年前就开始聚集淀粉样蛋白-β 的初始增加聚集的 tau 病理学。其他（p-tau205 和 t-tau）随着萎缩和代谢减退而增加，接近症状发作。这些发现提供了对连接 tau、淀粉样蛋白-β 和神经变性的途径的见解，并可能促进基于 tau 的治疗的临床试验。