show Abstracthide AbstractAlzheimer''s disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, the roles of immune cell subsets in AD onset and progression are poorly understood. By transcriptional single cell sorting, we comprehensively map all immune populations in wild type and AD–transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify the markers, spatial-location, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices showed DAM with intracellular/phagocytic Aß particles. Single cell analysis of DAM in Tg-AD and Trem2-/- Tg-AD revealed that the DAM program is activated in a two-step process. Activation is initiated in a Trem2 independent manner which involves down-regulation of microglia checkpoints, followed by activation of a Trem2-dependent program. These data identify a unique microglia-type, which may have important implications for future treatment of AD and other neurodegenerative diseases. Overall design: Transcriptional profiling of single cells from immune populations of mouse models of neurodegenerative diseases with matched controls, generated from deep sequencing of tens of thousands of cells, sequenced in several batches on illumina Nextseq500