Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.

指示阿尔茨海默病 (AD) 病理学的血液生物标志物在疾病的临床前阶段和症状阶段都会发生变化。独特的生物标志物可能是识别 AD 病理或监测疾病进展的最佳选择。与疾病过程中认知变化和萎缩相关的血液生物标志物可用于临床试验，以确定成功的干预措施，从而加速有效疗法的开发。当缓解疾病的治疗方法被批准使用时，有效的血液生物标志物也可能为临床实践中的治疗实施和管理提供信息。在 BioFINDER-1 队列中，血浆磷酸化 (p)-tau231 和淀粉样蛋白-β42/40 比率在淀粉样蛋白病理学阈值较低时变化更大。然而，纵向来看，只有 p-tau217 在 4-6 年内在疾病的临床前和症状阶段表现出明显的淀粉样蛋白依赖性变化，而在 p-tau231、p-tau181、淀粉样蛋白-β42/40、神经胶质细胞中没有观察到此类变化。酸性纤维蛋白或神经丝光。只有 p-tau217 的纵向增加也与临床前 AD 的临床恶化和脑萎缩有关。 p-tau217 的选择性纵向增加及其与认知能力下降和萎缩的关联在一个独立队列（威斯康星州阿尔茨海默病预防登记处）中得到证实。这些发现支持血浆生物标志物与疾病发展之间的差异关联，并强烈强调 p-tau217 作为临床前和前驱 AD 疾病进展的替代标志物，对新的疾病缓解疗法的开发具有影响。