Cognitive resilience — the absence of dementia despite extensive amyloid and tau pathology — was linked to the myocyte enhancer factor 2 (MEF2) gene family, researchers reported.
In two datasets totaling about 1,000 people, cognitive resilience was highly correlated with expression of MEF2 and many of the genes it regulates, according to Li-Huei Tsai, PhD, of Massachusetts Institute of Technology in Cambridge, and colleagues.
MEF2 also was more active in the brains of mice exposed to a cognitively stimulating environment, they reported in Science Translational Medicine. These mice performed better in learning and memory tasks.
The findings shed light on “the well-described phenomenon of cognitive resilience,” Tsai told MedPage Today.
“Both mouse and human experiments pointed to an important role for the MEF2 family of transcription factors in governing the cognitive benefits after environmental enrichment and mediating cognitive resilience to neurodegenerative pathology,” Tsai said.
The strongest epidemiological predictors of cognitive resilience are mentally stimulating activities including high education levels and cognitively demanding occupations. More recent research has shown that people who engage in cognitively stimulating activities have a lower risk of age-related memory loss. Some centenarians have shown high cognitive performance despite varying loads of amyloid beta, neurofibrillary tangles, and neuritic plaques.
This new research suggests a previously unappreciated role for MEF2 transcription factors and their potential as biomarkers or therapeutic targets, Tsai noted. “The fact that environmental enrichment has been shown to have protective effects in numerous mouse models including neurodegeneration, depression, and anxiety suggests that the molecular features recruited after enrichment, such as MEF2, may shed therapeutic insights into other neuropsychiatric symptoms beyond cognitive deficits in Alzheimer’s disease where hyperexcitability is a key feature,” she said.
In earlier research, the MEF2 family (MEF2A to MEF2D) has been implicated in neurodevelopment. Its transcriptional activity appears to be induced by neuronal activity, and genetic variants within the MEF2C locus have been linked with differences in human intelligence.
In their study, Tsai and colleagues used data from two repositories, including 260 individuals in the Mount Sinai Brain Bank and 636 people who participated in the Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal, clinical-pathological study. An analysis of ROSMAP data showed a significant (P<0.0001) positive correlation between cognitive activity and cognition.
Overall, cognitive function near the end of life was significantly correlated with beta-amyloid plaque density and tau burden, as expected. However, a small subset of people — less than 10% — showed cognitive resilience.
Increased expression of MEF2C and downstream targets were associated with both cognitive function and cognitive resilience. Single-cell RNA-sequencing of human brain cells showed MEF2 appeared to be most active in a subpopulation of excitatory neurons in the prefrontal cortex of resilient people.
Tsai and colleagues also compared mice raised in cages without toys to mice placed in a more stimulating environment with a running wheel and new toys every few days. MEF2 was more active in the brains of the mice exposed to the enriched environment.
Knocking out the gene for MEF2 in the frontal cortex blocked the mice’s ability to benefit from the enriched environment and their neurons became abnormally excitable. Overexpressing MEF2 in a mouse model of tauopathy improved cognitive flexibility and reduced hyperexcitability.
The findings suggest enhancing MEF2 activity could help protect against dementia, Tsai and colleagues said. Because MEF2 affects other types of cells and cell processes, more research is needed to make sure activating it would not have adverse effects, they added. The group hopes to identify how MEF2 becomes activated and plans to examine the effects of other genes MEF2 controls.
The work was funded by the Glenn Center for Biology of Aging Research, the National Institute on Aging, the Cure Alzheimer’s Fund, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Tsai disclosed serving on the scientific advisory boards of Cognito Therapeutics, Souvien Therapeutics, Cell Signaling Technology, Yumanity Therapeutics, Metro Bio, and Jupiter Neurosciences. Other researchers disclosed serving on the scientific advisory boards of AbbVie, Takeda, Origent, Vigorous Minds, and the NSF-Simons Center for Multiscale Cell Fate Research.