Language

English

Publication Date

8-7-2025

Journal

Cell Stem Cell

DOI

10.1016/j.stem.2025.06.006

PMID

40609533

PMCID

PMC12233156

PubMedCentral® Posted Date

1-30-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

Keywords

Animals, Dioxygenases, Alzheimer Disease, DNA-Binding Proteins, Phagocytosis, Mice, Humans, Myeloid Cells, Proto-Oncogene Proteins, Disease Progression, Mutation, Microglia, Disease Models, Animal, DNA Methyltransferase 3A, Male, Clonal Hematopoiesis, Central Nervous System, Mice, Inbred C57BL, Female, Brain, Clonal hematopoiesis, Alzheimer’s disease, inflammation, microglia, peripheral immune cells, myeloid cell activation, phagocytosis, DNMT3A, TET2

Comments

This article has been corrected. See Cell Stem Cell. 2025 Aug 1;32(9):1475.

Published Open-Access

yes

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