Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

中文翻译：

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脑脊液 tau 水平与阿尔茨海默病中的异常神经元可塑性标志物相关

脑脊液 (CSF) 中增加的总 tau (t-tau) 是阿尔茨海默病 (AD) 的一个关键特征，被认为是神经退行性疾病的结果。然而，T-tau 水平可以在非常早期的疾病阶段增加，此时神经变性是有限的，并且在晚期疾病阶段可以是正常的。这表明 t-tau 水平也可能由其他机制驱动。由于 tau 病理生理学正在成为 AD 的治疗目标，我们旨在阐明与 CSF t-tau 水平相关的分子过程。我们对 1380 名处于临床前、前驱期和轻度痴呆阶段的 AD 患者以及来自阿尔茨海默病神经影像学计划和 EMIF-AD 多模态生物标志物发现研究的 380 名对照进行了蛋白质组学、基因组学和影像学研究。我们发现，相对于对照，t-tau 增加的 AD 个体的 CSF 浓度增加了 400 多种富含神经元可塑性过程的蛋白质。相比之下，与对照组相比，t-tau 正常的 AD 个体的这些可塑性蛋白水平降低，并且表明血脑屏障和血脑脊液屏障功能障碍的蛋白质浓度增加。不同的蛋白质组学特征已经存在于临床前 AD 阶段，并持续存在于前驱期和痴呆阶段，这意味着它们反映了疾病特征而不是疾病状态。失调的可塑性蛋白与 SUZ12 和 REST 信号传导相关，表明异常的基因抑制。GWAS 分析对比了 t-tau 增加和不增加的 AD 个体，突出了几个参与基因表达调控的基因。GMNC 中 SNP rs9877502 的靶向分析与先前的 t-tau 水平相关，在 AD 个体中与 591 种可塑性相关蛋白的 CSF 浓度相关。然而，APOE-e4 等位基因的数量与可塑性相关蛋白的浓度无关。AD 中的 CSF t-tau 水平与参与神经元可塑性和血脑和血脑脊液屏障功能障碍的蛋白质水平改变有关。未来的试验可能需要对 CSF t-tau 状态进行分层，因为 t-tau 增加和 t-tau 正常的 AD 个体可能对治疗有不同的反应，因为他们的 CSF 蛋白质组学特征相反。与可塑性相关蛋白的浓度无关。AD 中的 CSF t-tau 水平与参与神经元可塑性和血脑和血脑脊液屏障功能障碍的蛋白质水平改变有关。未来的试验可能需要对 CSF t-tau 状态进行分层，因为 t-tau 增加和 t-tau 正常的 AD 个体可能对治疗有不同的反应，因为他们的 CSF 蛋白质组学特征相反。与可塑性相关蛋白的浓度无关。AD 中的 CSF t-tau 水平与参与神经元可塑性和血脑和血脑脊液屏障功能障碍的蛋白质水平改变有关。未来的试验可能需要对 CSF t-tau 状态进行分层，因为 t-tau 增加和 t-tau 正常的 AD 个体可能对治疗有不同的反应，因为他们的 CSF 蛋白质组学特征相反。