Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Disease-associated microglial subtype with elevated GPNMB expression, maintained by the upstream regulator MITF, whose neuroprotective effect depends on TREM2.

The authors profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of Alzheimer's disease neuropathology. Six subclasses comprising 13 transcriptionally distinct subtypes were delineated, with adaptive changes associated with aging and disease progression. A disease-associated microglial subtype characterised by elevated GPNMB expression and enriched for polygenic Alzheimer risk expands with pathology and shows increased phagocytic activity; MITF is identified as an upstream regulator required to maintain this state. Cell-cell interaction analyses prioritise APOE-SORL1 and APOE-TREM2 signalling pairs as associated with progression, and human and mouse models show that the neuroprotective effect of this microglial subtype depends on TREM2.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Nothing here changes a clinic appointment tomorrow, but the work provides a useful mechanistic frame for explaining to families why TREM2 and SORL1 variants matter: they hit a pathway whose cellular counterpart we can now see in human cortex. The limitation is that of any post-mortem atlas: subtypes are described on cross-sectional tissue, the inferred trajectory across aging remains correlative, and the link to polygenic risk is an enrichment association rather than a demonstration of causality. Worth following as a source of therapeutic targets rather than as a variant-level interpretation tool.

Analysis by Dr Thibaut Benquey