Somatic mutations reveal the ontogeny of microglia in human ageing

Microglia are the resident macrophages of the central nervous system¹. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis^2-4. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals^5-9. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.