Failures in Alzheimer's disease (AD) drug trials highlight the need to further explore disease mechanisms and alterations of biomarkers during the development of AD. Using cross-sectional data from 377 participants in the BioFINDER study, we examined seven cerebrospinal fluid (CSF) and six plasma biomarkers in relation to β-amyloid (Aβ) PET uptake to understand their evolution during AD. In CSF, Aβ42 changed first, closely followed by Aβ42/Aβ40, phosphorylated-tau (P-tau), and total-tau (T-tau). CSF neurogranin, YKL-40, and neurofilament light increased after the point of Aβ PET positivity. The findings were replicated using Aβ42, Aβ40, P-tau, and T-tau assays from five different manufacturers. Changes were seen approximately simultaneously for CSF and plasma biomarkers. Overall, plasma biomarkers had smaller dynamic ranges, except for CSF and plasma P-tau which were similar. In conclusion, using state-of-the-art biomarkers, we identified the first changes in Aβ, closely followed by soluble tau. Only after Aβ PET became abnormal, biomarkers of neuroinflammation, synaptic dysfunction, and neurodegeneration were altered. These findings lend in vivo support of the amyloid cascade hypotheses in humans.

中文翻译：

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在阿尔茨海默氏病中，随着淀粉样蛋白沉积的增加，脑脊液和血浆生物标志物的轨迹。

阿尔茨海默氏病（AD）药物试验的失败凸显了在AD发生过程中需要进一步探索疾病机制和生物标志物改变的需求。使用来自BioFINDER研究的377名参与者的横截面数据，我们检查了7种脑脊液（CSF）和6种血浆生物标志物与β淀粉样蛋白（Aβ）PET摄取的关系，以了解其在AD期间的演变。在脑脊液中，Aβ42首先改变，紧随其后的是Aβ42/Aβ40，磷酸化tau（P-tau）和总tau（T-tau）。在AβPET阳性后，脑脊液神经颗粒蛋白，YKL-40和神经丝光增加。使用来自五个不同制造商的Aβ42，Aβ40，P-tau和T-tau测定法重复了这些发现。对于脑脊液和血浆生物标志物，几乎同时观察到变化。总体而言，血浆生物标志物的动态范围较小，除了脑脊液和血浆P-tau相似外。总之，使用最新的生物标记物，我们确定了Aβ的第一个变化，紧随其后的是可溶性tau。只有在AβPET异常后，神经炎症，突触功能障碍和神经变性的生物标志物才发生改变。这些发现为人体内淀粉样蛋白级联假说提供了体内支持。