Somatic cancer variants enriched in Alzheimer's disease microglia-like cells drive inflammatory and proliferative states
Summary
Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood,
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# Somatic cancer variants enriched in Alzheimer's disease microglia-like cells drive inflammatory and proliferative states
*Published: 2026 Apr 21*
Alzheimer's disease (AD) is a neurodegenerative condition characterized by
microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311
brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs)
in cancer driver genes in AD brains, especially in genes associated with clonal
hematopoiesis (CH). These sSNVs were associated with clonal expansion and
carried by both microglia-like brain macrophages (MLBMs) in multiple brain
regions as well as paired blood, suggesting a likely hematopoietic origin.
Single-nucleus RNA sequencing data from 62 additional AD and control brains
revealed increased somatic copy number variants (sCNVs) associated with CH in AD
MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and
sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional
signatures characteristic of disease-associated microglia. These signatures were
recapitulated in induced pluripotent stem cell-derived microglia-like cells with
TET2, ASXL1, and DNMT3A variants. These findings suggest that clonal somatic
driver variants in MLBMs are enriched in AD, potentially promoting
neuroinflammation and neurodegeneration.
DOI: 10.1016/j.cell.2026.03.040