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

Alzheimer's disease (AD) therapies utilizing amyloid-ß (Aß) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aß clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aß 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 Aß clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aß 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 Aß removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aß clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aß removal and shed light on the role of microglia in immune-mediated Aß clearance. Importantly, our work uncovers potential molecular targets that could enhance Aß-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD. Overall design: 3 samples: 2 AD Non-Immunized AD (nAD); 1 lecanemab immunized AD (LCMB)