Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease [dataset3]

Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized AD patients with nonimmunized AD patients and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD. 4 donors, 4 brain areas: Left Middle Frontal Gyrus, Left Superior Temporal Gyrus, Left Inferior Parietal Lobule, Posterior Hippocampus of 3 nAD donors and 1 lecanemab-immunized AD donor Please note that Seurat object(s) were removed on March 17, 2025, as they were uploaded prior to revisions and contained outdated cell/spot annotations. Any Seurat objects downloaded before this date should not be used. For access to updated Seurat objects, please contact [e-mail].