A multi-pronged human microglia response to Alzheimer’s disease Aβ pathology

Microglial activation and neuroinflammation are initial steps in the pathogenesis of Alzheimer’s disease (AD). However, studies in mouse models and human postmortem samples have yielded divergent results regarding microglia cell states relevant to AD. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for early AD. While human microglia adopt a disease-associated (DAM) profile, they display a much more pronounced HLA-cell state related to antigen presentation in response to amyloid plaques. In parallel, a distinctive pro-inflammatory cytokine and chemokine CRM response is mounted against oligomeric amyloid-β. TREM2 and, to a lesser extent, APOE polymorphisms, modulate the response of microglia to amyloid-β plaques, in contrast with the response to oligomeric Aβ. Specific polygenic risk genes are enriched in each branch of these multi-pronged response of human microglia to amyloid pathology (ARM). ARM responses can be captured in post-mortem studies when reanalyzed in light of this novel, comprehensive data set. In conclusion, therapeutic strategies targeting microglia in AD need to carefully assess how they affect the different cell states, as the overall balance between distinct microglial profiles might determine a protective or damaging outcome. ### Competing Interest Statement B.D.S. is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. B.D.S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics.