Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer’s disease (AD) or Parkinson’s disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCγ2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCγ2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.

外周血单核细胞 (PBMC) 可以帮助深入了解阿尔茨海默病 (AD) 或帕金森病 (PD) 的发病机制。我们使用七种典型的免疫刺激剂、对 35 个 PBMC 子集进行质量流式细胞术鉴定、对 15 个细胞内信号标记进行单细胞定量，研究了来自 132 名研究参与者的 PBMC 样本，然后开发了机器学习模型以提高预测能力。由此，与对照组相比，在 AD 患者的 PBMC 子集中特别鉴定出三种主要的细胞内信号通路：许多细胞类型和刺激中 PLCγ2 的激活减少，以及 STAT1 和 STAT5 的选择性可变激活，具体取决于刺激物和细胞类型。我们的研究结果在功能上支持了现已经过多重验证的观察结果，即PLCG2中的罕见编码变异与 AD 风险降低相关。总之，这些数据表明增强的 PLCγ2 活性可作为 AD 的潜在新治疗靶点，具有易于获得的药效生物标志物。