20206-06-11 マウントサイナイ医療システム（MSHS）
＜関連情報＞
- https://www.mountsinai.org/about/newsroom/2026/cancer-associated-mutations-in-brain-immune-cells-may-contribute-to-alzheimers-disease
- https://www.cell.com/cell/fulltext/S0092-8674(26)00341-7
アルツハイマー病のミクログリア様細胞に多く見られる体細胞癌変異は、炎症および増殖状態を促進する Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states
August Yue Huang ∙ Zinan Zhou ∙ Maya Talukdar ∙ … ∙ Eirini P. Papapetrou ∙ Eunjung Alice Lee ∙ Christopher A. Walsh
Cell Published:April 21, 2026
DOI:https://doi.org/10.1016/j.cell.2026.03.040
Graphical abstract
Highlights
- Somatic variants linked to clonal hematopoiesis are elevated in Alzheimer’s brains
- These driver variants are carried by microglia-like macrophages across brain regions
- Mutant microglia-like macrophages display disease-related signatures in vivo
- iPSC-derived microglia-like cells with driver mutations recapitulate these signatures
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, 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.
