Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and prominent neuroimmune remodeling, but the contribution of macrophage and myeloid states across disease severity remains incompletely defined. We integrated bulk transcriptomic, single-cell RNA sequencing (RNA-seq), and spatial transcriptomic datasets to characterize AD-associated myeloid immune changes across Braak stage and disease status. Across datasets, M2-like macrophage and myeloid signatures showed progressive enrichment with increasing neuropathological severity and were accompanied by pathway changes related to macrophage proliferation, TGF-β signaling, and myeloid homeostasis. Immune-feature-based classifiers identified macrophage-related variables among the informative features distinguishing AD from controls. CellChat analyses further inferred that M2-like myeloid populations occupied communication-enriched positions in single-cell and spatial interaction networks, including apolipoprotein E (ApoE), CX3C chemokine signaling, and fibronectin 1 (FN1)-associated signaling contexts. Collectively, these findings indicate that M2-like myeloid programs are consistently associated with AD severity and neuroimmune network remodeling. Rather than establishing a causal disease driver, this study highlights M2-like myeloid signatures as candidate neuroimmune components that warrant experimental validation in human-relevant systems.
Wang et al. (Fri,) studied this question.
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