Study Links TET2 Mutations in Blood Stem Cells to Reduced Alzheimer's Risk

A recent study published in the journal *Cell Stem Cell* suggests that mutations in blood stem cells may offer protection against late-onset Alzheimer's disease. Led by a team from Baylor College of Medicine, the research reveals that individuals with mutations in the TET2 gene—found within hematopoietic stem cells—exhibit a significantly lower risk of developing Alzheimer's compared to those with mutations in the DNMT3A gene.

The study's lead author, Dr. Katherine King, a professor of pediatrics-infectious diseases and a member of the Center for Cell and Gene Therapy at Baylor College of Medicine, stated, "Our lab has long been studying blood stem cells. These mutations, particularly in TET2, appear to have protective properties against Alzheimer's disease."

Hematopoietic stem cells, residing in the bone marrow, are crucial for generating various blood cell types necessary for maintaining health. As individuals age, these stem cells can develop mutations, a phenomenon known as clonal hematopoiesis, which occurs in approximately 20% of those aged 70 and older. While clonal hematopoiesis has been associated with increased risks for cardiovascular diseases and blood cancers, its relationship with Alzheimer's disease remains poorly understood.

According to Dr. Katie A. Matatall, the first author of the study, the research focused on the two genes most commonly mutated in clonal hematopoiesis—TET2 and DNMT3A—due to their involvement in inflammation, a process known to be heightened in Alzheimer's patients. The researchers utilized data from the UK Biobank and conducted experiments on mouse models of Alzheimer's disease, discovering that TET2 mutations correlate with a 47% reduction in the risk of developing the disease in humans.

The team found that TET2-mutant bone marrow transplants in mice resulted in reduced cognitive decline and lower levels of beta-amyloid plaques, which are characteristic of Alzheimer's disease. Notably, these effects were not replicated with DNMT3A mutations. Furthermore, the protective mechanism appeared to involve TET2-mutant stem cells' enhanced ability to migrate into the brain, where they effectively cleared beta-amyloid deposits more efficiently than their non-mutant counterparts.

This groundbreaking study marks the first instance of demonstrating that specific mutations in blood stem cells can influence disease outcomes differently. As Dr. King emphasizes, "We need to consider clonal hematopoiesis from a mutation-specific perspective to accurately assess its risks and benefits."

The findings of this study could pave the way for new therapeutic strategies aimed at mitigating the risks associated with degenerative diseases of the central nervous system. Future research will be needed to explore the implications of these mutations more thoroughly and to understand how they can be harnessed for Alzheimer's prevention and treatment.

In conclusion, this study not only sheds light on the complex relationship between blood stem cell mutations and Alzheimer's disease but also underscores the potential for targeted therapies that could leverage these genetic insights to improve patient outcomes in neurodegenerative disorders.