Unexpected mutations in blood stem cells may help protect against Alzheimer’s disease.
A new study published in the journal Cell Stem Cell suggests that certain genetic changes in blood stem cells may offer protection against late-onset Alzheimer’s disease.
Researchers from Baylor College of Medicine found that both mice and humans with blood stem cells carrying mutations in the gene TET2 (but not in DNMT3A) were less likely to develop Alzheimer’s. The findings point to a potential protective mechanism and may lead to innovative approaches for slowing or preventing the onset and progression of this serious neurological disorder.
“Our lab has long been studying blood stem cells, also called hematopoietic stem cells,” said lead author Dr. Katherine King, professor of pediatrics – infectious diseases and a member of the Center for Cell and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center at Baylor. She also is part of Texas Children’s Hospital.
Hematopoietic stem cells live in the bone marrow and generate all the different types of blood cells the body needs to stay alive and healthy – red blood cells, immune cells, and platelets. As people get older, blood stem cells can develop mutations, and this occurs in about 20% of 70-year-olds. Most of the time, these mutations don’t cause problems, but sometimes, a mutation drives the cells to divide more than others, forming a clone.
This process is called clonal hematopoiesis and it has been linked to a higher risk for conditions such as cardiovascular disease, stroke, blood cancers like leukemia, and chronic obstructive pulmonary disease.
Linking Clonal Hematopoiesis to Alzheimer’s
However, many questions remain regarding the connection between clonal hematopoiesis and Alzheimer’s disease.
“In the current study, we investigated the effect of the two genes most commonly mutated in clonal hematopoiesis, TET2 and DNMT3A, on Alzheimer’s disease,” said first author Dr. Katie A. Matatall, instructor in the King lab. “We also selected these mutations because they are involved in inflammation, which is known to be increased in Alzheimer’s disease.”
The researchers assessed the effect of clonal hematopoiesis on the prevalence of Alzheimer’s disease using human data stored in the UK Biobank. They also evaluated the role of mutations in genes Tet2 and Dnmt3a in a mouse model of Alzheimer’s disease.
The team discovered that the two mutations do not behave the same way. Clonal hematopoiesis with the TET2-mutant was associated with a 47% reduced risk of late-onset Alzheimer’s disease in humans, whereas other mutations of clonal hematopoiesis did not confer protection. In a mouse model, transplantation of Tet2-mutant bone marrow reduced cognitive decline and beta-amyloid plaque formation, effects not observed with Dnmt3a-mutant cells.
How TET2 Mutations Help
“Furthermore, we found that the protective effect seemed to be mediated by TET2-clonal stem cells circulating in the blood,” Matatall said. “Immune cells derived from these clones were able to migrate into the brain where they cleared beta-amyloid deposits, a hallmark of Alzheimer’s disease, more effectively than cells without the TET2 mutation. We think that it’s both the increased migration into the brain and the enhanced ability to clear Alzheimer’s-associated damage that drives the better outcomes.”
“Until now, clonal hematopoiesis has primarily been associated with promoting the progression of disease. This is the first time that these two mutations in blood stem cells have been shown to influence disease in different ways,” King said. “The findings show that some clonal hematopoiesis promote disease while others, like TET2, may provide protection. We need to think about clonal hematopoiesis in a mutation-specific way and assess their risks and benefits.”
The findings establish a novel experimental platform for understanding the role of clonal hematopoiesis in Alzheimer’s disease and may inform future approaches to mitigate the risks of central nervous system degenerative diseases.
Reference: “TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice” by Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid and Katherine Y. King, 2 July 2025, Cell Stem Cell.
DOI: 10.1016/j.stem.2025.06.006
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