Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimer’s Disease Tissue

Using microglia-enriched spatial transcriptomics on human Alzheimer’s disease tissue, we identify distinct gene expression changes across microglia located in direct contact with plaques, in periplaque regions, and in areas distant from plaques. We define a group of plaque contact–only microglial (PCOM) genes whose expression increases exclusively in microglia directly contacting plaques. These genes show significant overlap with previously reported gene sets, suggesting that plaque-contacting microglia correspond to the well-characterised disease-associated microglia (DAM) and other AD-related gene-expression signatures. We further identify distinct co-expression networks associated with disease-relevant covariates, including an immune module linked to APOE genotype and a synaptic–mitochondrial module negatively associated with Braak stage. Finally, we compare the human dataset to our previously published data from 18-month-old AppNL-F mice, generated using the same experimental paradigm and demonstrate cross-species concordance in gene expression within plaque-contacting microglia. NanoString GeoMx Digital Spatial Profiler (DSP) was applied to FFPE human hippocampus to profile microglia-enriched gene expression from donors with Alzheimer’s disease (AD) and cognitively unimpaired, amyloid-positive (CU-AP) controls. For each tissue, gene expression was captured from microglia directly contacting amyloid plaques (“plaque-associated”), (ii) microglia in the peri-plaque region, and (iii) microglia distant from plaques.