Adolescence is a critical phase in human brain development, but some of the mechanisms governing the boost in cognition have been difficult to probe without invasive methods. Now, researchers report that epigenetic changes detectable in saliva are responsible for key aspects of white matter development in the adolescent brain, offering a non-invasive window into the processes shaping cognition.
One epigenetic mechanism involves the addition or removal of chemical tags, such as a methyl group, to DNA, changing how genes work without altering the actual genetic code. These markers of epigenetics can now be detected in blood or saliva, directly signaling their presence in brain tissues.
Dawn Jensen, a researcher at Georgia State University in the United States, and colleagues previously found that changes in DNA methylation in seven genes, which are highly expressed in the brain, are linked to the development of grey matter in the brain as well as improved cognition. The team wanted to expand this research by drawing links between DNA methylation changes in the same seven genes and white matter development.
For the study, the researchers used a neuroimaging technique called fractional anisotropy. It is used to analyze the maturation and integrity of the brain’s white matter. In general, fractional anisotropy changes rapidly from birth, with the greatest jumps during the first three years, plateauing around five years of age. While not as massive, another spike occurs during adolescence, continuing into a person’s 20s.
The team used data that was collected as part of a longitudinal cohort study, Developmental Chronnecto-Genomics (Dev-CoG), of about 200 children between the ages of 9 and 14 years. At three different time points during the study period, data on neuroimaging and cognitive testing as well as saliva samples were collected.
The researchers found a definite pattern: as the methyl tags on the genes became less abundant, evidence of brain development and cognitive improvements grew. These genes are critical for insulation of axons, called myelination, speeding up and refining communication across the brain. Specifically, these developments occurred in four brain networks, including the corpus callosum, a structure that bridges the two hemispheres, as well as the posterior thalamic radiation, critical for conducting sensory and motor information. Other areas like the tapetum and white matter tracts in the cuneus and superior lateral occipital cortices also matured, as measured by changes in fractional anisotropy. Maturation in these areas brings better efficiency and with it, stronger executive function and working memory.
Notably, the researchers found that changes in fractional anisotropy, a marker of brain maturation, were the mediating factor between changes in methylation and cognitive development. Decreases in methylation at DNA segments in several genes were linked to increases in fractional anisotropy. Moreover, elevated fractional anisotropy measures in the corpus callosum and posterior thalamic radiation were directly linked to both better cognition and lower methylation in genes responsible for myelination and axonal signaling.
“This same network of white matter maturation also mediates the relationship between the demethylation of these genes and improvements in overall cognitive performance during adolescence,” write the researchers. “These findings offer new research directions from which a more detailed understanding of the molecular underpinnings of the drivers of adolescent brain development may emerge.”
Key Reference: Dawn Jensen et al., Adolescent White Matter Maturation Mediates Epigenetic Associations with Cognitive Development, Developmental Neurobiology (2025). DOI: https://onlinelibrary.wiley.com/doi/10.1002/dneu.70000
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