APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease

Acta Neuropathol. 2020 Oct;140(4):477-493. doi: 10.1007/s00401-020-02200-3. Epub 2020 Aug 25.


Beta-amyloid deposition is a defining feature of Alzheimer's disease (AD). How genetic risk factors, like APOE and TREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with varied APOE and TREM2 genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases with APOE and TREM2 risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating that APOE and TREM2 risk variants are associated with a significant reduction in CD163-positive amyloid-responsive microglia. Our results showcase the diverse microglial response in AD and underscore how genetic risk factors influence cellular responses to underlying pathologies.

Keywords: APOE; Alzheimer’s disease; Microglia; TREM2; Transcriptomics; snRNA-seq.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Apolipoproteins E / genetics*
  • Humans
  • Membrane Glycoproteins / genetics*
  • Microglia / pathology*
  • Receptors, Immunologic / genetics*


  • Amyloid beta-Peptides
  • ApoE protein, human
  • Apolipoproteins E
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human