Summary: A new study identifies a genetic mutation that may influence the severity of chronic traumatic encephalopathy (CTE).
Source: Boston University School of Medicine.
Researchers identify a genetic variation in TMEM106B that may affect CTE severity and risk of dementia
Researchers have reported a genetic variation in the gene TMEM106B that appears to influence the severity of chronic traumatic encephalopathy (CTE) and the likelihood of dementia in people with CTE. TMEM106B has emerged as one of the first genes linked to CTE pathology and may help explain why some athletes and others exposed to repetitive head impacts develop severe symptoms while others with similar exposure remain less affected.
In this study, investigators from Boston University School of Medicine (BUSM) and the VA Boston Healthcare System examined brain tissue donated to the VA-BU-CLF brain bank. The research focused on 86 former contact-sport athletes whose brains showed CTE pathology but no other major neuropathology. The team analyzed genetic variation in TMEM106B, a gene that has been implicated in neuroinflammatory processes, and evaluated its relationship to CTE pathology, markers of inflammation, and clinical dementia.
The researchers found that, overall, the frequency of TMEM106B variation did not differ between individuals with CTE and those without CTE. However, when the analysis was restricted to athletes who had CTE, the presence of the TMEM106B risk allele was associated with more severe CTE pathology and increased measures of brain inflammation. In addition, carriers of the risk variant were approximately 2.5 times more likely to have developed dementia, suggesting the variant could predict increased clinical severity among people with established CTE.
Jonathan Cherry, PhD, postdoctoral fellow in neurology at BUSM and the study’s first author, noted that these results are preliminary but point to a potential role for TMEM106B variation in modifying disease expression. Thor Stein, MD, PhD, neuropathologist at VA Boston Healthcare System and assistant professor of pathology and laboratory medicine at BUSM, emphasized that understanding genetic differences that influence vulnerability could open new avenues for identifying therapeutic targets and developing biomarkers detectable during life.
The authors stress caution in interpreting the findings for individual prediction. At present, it remains unclear what the presence of the TMEM106B risk allele means for any single person exposed to repetitive head impacts. The study does not support clinical genetic testing for TMEM106B as a routine tool for assessing CTE risk or prognosis. Instead, the findings should be viewed as an early step toward understanding biological mechanisms that underlie variable outcomes following similar exposures.
Co-first author Jesse Mez, MD, MS, assistant professor of neurology at BUSM, contributed to study design and analysis. Ann McKee, MD, Chief of Neuropathology at VA Boston Healthcare System and Director of the BU CTE Center, served as co-senior author. The research was conducted using brain tissue donated to the VA-BU-CLF brain bank and included neuropathological assessment combined with genetic analysis focused on TMEM106B.
Implications: These findings offer preliminary evidence that genetic variation can modify CTE severity and associated dementia risk. If replicated in larger and more diverse cohorts, the results could inform development of biomarkers for diagnosis during life and point to molecular pathways for therapeutic intervention. Until further validation, however, the presence of the TMEM106B variant should not be used to make clinical decisions or to provide individualized risk estimates.
Funding: This research received support from multiple sources including the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the U.S. Department of Defense, the U.S. Department of Veterans Affairs, Veterans Affairs Biorepository programs, Veterans Affairs Rehabilitation Research and Development, the Department of Defense Chronic Effects of Neurotrauma Consortium, the National Center for PTSD, the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association, several private foundations, and sports organizations. Funding supported brain banking, neuropathology, genetic analysis, and data interpretation.
Presentation and publication: The study was presented at Neuroscience 2018, the annual meeting of the Society for Neuroscience, and the results will appear in Acta Neuropathologica Communications. These venues ensure peer engagement and further scientific scrutiny of the findings.
Authors and contact: Study authors include Jonathan Cherry, PhD; Jesse Mez, MD, MS; Thor Stein, MD, PhD; Ann McKee, MD; and other collaborators at BUSM and VA Boston Healthcare System. The work was organized and reported by investigators affiliated with Boston University School of Medicine and the VA-BU-CLF brain bank.
Boston University School of Medicine. “Genetic Risk Factor for CTE Detected.” NeuroscienceNews. November 2, 2018.