Healthcare (Commonwealth Union) – Recent research that was featured in Cell Stem Cell suggests that certain genetic changes in blood-forming stem cells could guard against the late-onset of Alzheimer’s disease.
Researchers from Baylor College of Medicine, who led the investigation, found that both mice and humans with blood stem cell mutations in the TET2 gene—but not in DNMT3A—appeared to have a reduced likelihood of developing Alzheimer’s. The findings point to a potential biological pathway that could shield against the condition and pave the way for innovative treatment approaches to delay or prevent its progression.
Dr. Katherine King, the study’s senior author and a professor of pediatrics specializing in infectious diseases at Baylor and a member of both the Center for Cell and Gene Therapy the Dan L Duncan Comprehensive Cancer Center. She is also affiliated with Texas Children’s Hospital and indicated that their research has focused extensively on hematopoietic stem cells, which are the blood-producing cells found in bone marrow.
Hematopoietic stem cells, found in the bone marrow, are responsible for producing all the various blood cells essential for survival and good health — including red blood cells, immune cells, and platelets. As people age, these stem cells can acquire genetic mutations, which occur in roughly 20% of individuals by the age of 70. While most of these mutations are harmless, some can cause certain stem cells to multiply more than others, leading to the formation of a dominant group of cells, or a “clone.” This phenomenon is known as clonal hematopoiesis and has been associated with an increased risk of health issues such as heart disease, stroke, blood cancers like leukemia, and chronic obstructive pulmonary disease (COPD). Despite these findings, the link between clonal hematopoiesis and Alzheimer’s disease is still not fully understood.
Dr. Katie A. Matatall, lead author and instructor in the King lab indicated that in this study, they examined how mutations in the two most frequently altered genes in clonal hematopoiesis — TET2 and DNMT3A — influence the development of Alzheimer’s. She further stated that they focused on these particular mutations because they play a role in inflammation, which is a known factor in Alzheimer’s disease.
The scientists investigated how clonal hematopoiesis influences the risk of developing Alzheimer’s disease by analyzing human data from the UK Biobank. They also examined the impact of mutations in the Tet2 and Dnmt3a genes using a mouse model of Alzheimer’s.
Their findings showed that the two mutations had different outcomes. In humans, clonal hematopoiesis involving a TET2 mutation was linked to a 47% lower likelihood of developing late-onset Alzheimer’s disease, while other types of clonal hematopoiesis mutations offered no such protection. In mice, transplanting bone marrow with the Tet2 mutation helped prevent memory loss and the build-up of beta-amyloid plaques—benefits that were not seen with Dnmt3a-mutant bone marrow.
“Furthermore, we found that the protective effect seemed to be mediated by TET2-clonal stem cells circulating in the blood,” added Matatall. “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.”
King indicated that up to this point, clonal hematopoiesis has mostly been linked to worsening disease and is the first evidence showing that two specific mutations in blood stem cells can have distinct effects on disease. She further indicated that these results suggest that while some forms of clonal hematopoiesis contribute to disease, others—like those involving TET2—might actually offer protection and it is important to evaluate each mutation individually to understand their potential risks and benefits.
