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

Abstract

Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the underlying mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we employ spatial transcriptomics (ST) to explore the effects of both active and passive Aβ immunization on the AD brain. Comparing actively immunized AD patients with non-immunized AD subjects and neurologically healthy controls, we identify distinct microglial states associated with Aβ clearance. Using high-resolution ST alongside single-cell RNA sequencing (scRNA-seq), we delve deeper into the transcriptional pathways involved in Aβ removal following treatment with lecanemab, uncovering spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Apolipoprotein E (APOE) in microglia across both active and passive immunization approaches, which correlate positively with Aβ clearance. These findings provide novel insights into the transcriptional mechanisms orchestrating Aβ clearance and shed light on the role of microglia in immune-mediated 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. This study paves the way for future research into microglial modulation and its therapeutic potential in AD.

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Identifiers

ORCID for James A.R. Nicoll: orcid.org/0000-0002-9444-7246

ORCID for Delphine Boche: orcid.org/0000-0002-5884-130X

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