A major hallmark of Alzheimer’s disease (AD) is the aggregation of proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain, which makes the AD proteome in cerebrospinal fluid (CSF) of particular interest. Here, we conducted a CSF proteome-wide analysis among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), using a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. We identified 61 proteins significantly associated with AT category (P < 5.46 x 10^-5; strongest was SMOC1, P = 1.87 x 10^-12) and 636 significant protein-biomarker associations (P < 6.07 x 10^-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10^-25). Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks centered around amyloid and tau measures, neurogranin, and the remaining biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were associated with CSF phosphorylated tau levels in an independent replication cohort of 717 participants (P = 8.65 x 10^-56 and P = 1.35 x 10^-45). Follow-up interrogation of related CSF metabolite levels in the same samples as the discovery proteomics analysis identified increasing levels of succinylcarnitine with ptau and numerous other CSF biomarkers (P < 0.00056) that were replicated in an independent sample of 363 participants. Together, these results implicate glucose metabolic dysregulation and increased CSF succinylcarnitine levels as amyloid and tau pathology emerge in AD.

中文翻译：

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脑脊液的大规模蛋白质组和代谢组分析表明阿尔茨海默病中葡萄糖代谢和琥珀酰肉碱的改变

阿尔茨海默病 (AD) 的一个主要标志是大脑中蛋白质（β-淀粉样蛋白 (A) 和过度磷酸化 tau (T)）的聚集，这使得脑脊液 (CSF) 中的 AD 蛋白质组特别受关注。在这里，我们对患有和不患有 AD 病理学的参与者（n = 137 名参与者：56 名 AT-、39 名 A+T- 和 42 名 A+T+；分析了 915 种蛋白质）进行了 CSF 蛋白质组范围的分析，使用了一组 9用于神经变性和神经炎症的脑脊液生物标志物。我们鉴定了 61 种与 AT 类别显着相关的蛋白质（P < 5.46 x 10 ^-5；最强的是 SMOC1，P = 1.87 x 10 ^-12）和 636 种显着的蛋白质-生物标志物关联（P < 6.07 x 10 ^-6；最强的是阳性神经颗粒蛋白和 EPHA4 之间的关联，P = 2.42 x 10^-25 )。社区网络和通路富集分析强调了三个以淀粉样蛋白和 tau 测量、神经颗粒蛋白和其余生物标志物为中心的生物标志物相关蛋白网络。葡萄糖代谢途径主要在淀粉样蛋白和 tau 相关蛋白中富集，包括苹果酸脱氢酶和醛缩酶 A，在 717 名参与者的独立复制队列中，这两者都与 CSF 磷酸化 tau 水平相关（P = 8.65 x 10 ^-56和P = 1.35 x 10 ^-45）。对与发现蛋白质组学分析相同的样本中相关 CSF 代谢物水平的后续询问发现，具有 ptau 和许多其他 CSF 生物标志物的琥珀酰肉碱水平不断增加（P < 0.00056），这些生物标志物在 363 名参与者的独立样本中得到了复制。总之，这些结果暗示葡萄糖代谢失调和脑脊液琥珀酰肉碱水平升高，因为淀粉样蛋白和 tau 病理学出现在 AD 中。