Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

中文翻译：

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阐明 CSF Aβ、tau、BACE1 和神经颗粒蛋白与阿尔茨海默病 AT（N） 分期的相关性


目前阿尔茨海默病 （AD） 的 AT（N） 分层解释了淀粉样蛋白 （A）、tau 蛋白病 （T） 和神经变性 （N） 特征的复杂组合。了解这些不同阶段之间的过渡是一项重大挑战，尤其是考虑到疾病修饰疗法的最新发展。这是一项观察性研究，在认知障碍患者的 BALTAZAR 队列和阿尔茨海默病神经影像学倡议 （ADNI） 中测量了 Tau、pTau181、pTau217、Aβ38/40/42、sAPPα/β、BACE1 和神经颗粒蛋白的 CSF 水平。生物标志物水平与 AT（N） 框架相关。（A） 和 （T） 在 BALTAZAR 中分别定义为 CSF Aβ42/40 比值和 pTau217，在 ADNI 中分别定义淀粉样蛋白和 tau PET。（N） 使用两个队列中的总 CSF tau 定义。正如预期的那样，CSF Aβ42 随着 AD 连续体从 A-T-N- 到 A + T + N + 曲线而逐渐降低。另一方面，Tau 和 pTau181 随着疾病的发生而逐渐增加。从 A + T + N- 到 A + T + N + 的最终转变导致 Aβ38、Aβ42 和 sAPP 水平急剧增加。突触 CSF 生物标志物 BACE1 和神经颗粒蛋白在初始 A + T-N- 阶段最低，随 T + 和 N + 的增加而增加。CSF pTau181 和总 tau 在两个队列中均密切相关。向 A + 表型 （A + TN-） 的早期转变主要影响突触功能。T + 然后 N + 的出现与病理阿尔茨海默病生物标志物的显着和进行性增加有关。我们的主要发现是 CSF pTau181 是 N + 而不是 T + 的指标，并且 N + 与 BACE1 蛋白和 β-淀粉样蛋白肽水平升高有关。这种增加可能会在正反馈回路中推动淀粉样蛋白级联反应。 总体而言，我们的数据为了解阿尔茨海默病潜在淀粉样蛋白、 tau 蛋白和神经变性相互关联的病理过程提供了进一步的见解。