Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
Department of Neurology, Skåne University Hospital, Lund, Sweden.
EMBO Mol Med. 2019 Dec;11(12):e11170. doi: 10.15252/emmm.201911170. Epub 2019 Nov 11.
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.
阿尔茨海默病（AD）药物试验的失败凸显了进一步探索疾病机制和 AD 发展过程中生物标志物变化的必要性。我们利用 BioFINDER 研究中 377 名参与者的横断面数据，研究了与β-淀粉样蛋白（Aβ）PET 摄取相关的七种脑脊液（CSF）和六种血浆生物标志物，以了解它们在 AD 期间的演变。在 CSF 中，Aβ42 首先发生变化，紧随其后的是 Aβ42/Aβ40、磷酸化tau（P-tau）和总 tau（T-tau）。在 Aβ PET 阳性点之后，CSF 神经颗粒蛋白、YKL-40 和神经丝轻链增加。使用来自五个不同制造商的 Aβ42、Aβ40、P-tau 和 T-tau 检测方法复制了这些发现。CSF 和血浆生物标志物的变化几乎同时发生。总体而言，除了 CSF 和血浆 P-tau 相似外，血浆生物标志物的动态范围较小。总之，使用最先进的生物标志物，我们确定了 Aβ 的最早变化，紧随其后的是可溶性 tau。只有在 Aβ PET 变得异常后，神经炎症、突触功能障碍和神经退行性变的生物标志物才会发生改变。这些发现为人类的淀粉样蛋白级联假说提供了体内支持。
