Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease

Alzheimer's disease (AD) therapies utilizing amyloid-beta (A beta) immunization have shown potential in clinical trials. Yet, the mechanisms driving A beta clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive A beta immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with A beta clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in A beta 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 A beta removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to A beta clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating A beta removal and shed light on the role of microglia in immune-mediated A beta clearance. Importantly, our work uncovers potential molecular targets that could enhance A beta-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.