Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages.

蛋白质组学可以揭示阿尔茨海默病 （AD） 等神经退行性疾病的动态和多方面变化。将测量 β-淀粉样蛋白 （Aβ） 斑块和 tau 缠结的放射配体与脑脊液蛋白质组学相结合，我们揭示了反映活人 AD 病理不同阶段的分子事件。我们在整个 AD 谱中发现了 127 种差异丰度蛋白 （DAP）。最强的 Aβ 相关蛋白主要在神经胶质细胞中表达，包括 SMOC1 和 ITGAM。十几种与 ATP 代谢相关并优先在神经元中表达的蛋白质与 tau 缠结负荷和 tau 积累独立相关。在其他神经退行性疾病中，只有 20% 的 DAPs 也发生了改变，这凸显了 AD 独特的蛋白质组。分别与蛋白质代谢和小胶质细胞免疫反应相关的两个共表达模块包含大多数 DAP，沿 AD 连续体具有相反的交错轨迹。我们揭示了与体内 Aβ 和 tau 蛋白病相关的蛋白质特征，提供了对复杂神经反应以及针对不同疾病阶段的潜在生物标志物和疗法的见解。