A study published in Cell Stem Cell reveals that some mutations in blood stem cells might help protect against late-onset Alzheimer’s disease.
A team led by researchers at Baylor College of Medicine discovered that both a mouse model and people carrying blood stem cells with mutations in the gene TET2, but not in the gene DNMT3A, had a lower risk for developing Alzheimer’s disease. Their study proposes a mechanism that can protect against the disease and opens new avenues for potential strategies to control the emergence and progression of this devastating condition.
“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. 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.
“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. 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.”
Dr. Katherine King, professor of pediatrics – infectious diseases, Baylor College of Medicine
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.
Source:
Baylor College of Medicine
Journal reference:
Matatall, K. A., et al. (2025). TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice. Cell Stem Cell. doi.org/10.1016/j.stem.2025.06.006.