Spatial transcriptomics reveals microglial mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients.

Current Alzheimer's disease (AD) therapeutics include immunization against amyloid-β (Aβ). Post-mortem brain analyses from the first active Aβ immunotherapy clinical trial (AN-1792) indicate clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain undiscovered. Here, we used spatial transcriptomics to study brain tissues from 13 AD patients actively immunized with Aβ. We compared actively immunized patient brains to brains from non-immunized AD patients and non-neurologic disease controls. Additionally, we used spatial proteogenomics and single-cell RNA sequencing to investigate mechanisms of Aβ clearance following administration of lecanemab, a passive anti-Aβ therapeutic. We reveal the microglial response mediating Aβ clearance following immunization against Aβ. This microglial response is defined by upregulated expression of Triggering Receptor Expressed On Myeloid Cells 2, Apolipoprotein C1, Alpha-2-Macroglobulin and RAB13, Member RAS Oncogene Family. Altogether, these data uncover molecular mechanisms by which microglia clear Aβ in the AD brain following immunization.