APOEε4 may confer increased risk for CTE-related neuropathological outcomes among older adults with repetitive head impacts

Reviewed by Emily Henderson, B.Sc.Jun 27 2022

How could two individuals who both played football for 10 years and developed CTE have different disease severity? How could some individuals develop dementia in their 50's while other never develop dementia at all? Perhaps the answer lies in their genes.

Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure.

Now a new study from researchers from the BU CTE Center reveals that the genetic variant, APOEε4 plays a major role in determining CTE severity and that having APOEε4 makes an individual 2.34 times more likely to develop a more severe form of CTE.

This study provides the most concrete evidence to date that APOEε4 is a risk factor for CTE-related pathological and clinical outcomes. Understanding genetic underpinnings of CTE pathology may provide insights into disease mechanism and offers a precision medicine approach to harm reduction, including guiding decisions regarding contact sport play and providing a target for therapies."

Jesse Mez, MD, MS, corresponding author, director of the Boston University (BU) Alzheimer's Disease Research Center Clinical Core and a BU CTE Center investigator

The researchers studied the brains of deceased individuals exposed to RHI through contact sports or military service, 294 of whom developed CTE and 70 of whom did not. They then analyzed their neurological findings based on their APOE status and found that APOEε4 carriers were 2.34 times more likely to have more severe CTE than those without. More severe CTE was determined by both CTE Stage (I through IV) and a quantitative analysis of abnormal tau protein burden.

"Our research team has shown that among football players, an individual's odds of developing a more severe stage of CTE double every additional 4.4 years of play. Specifically, for football players over age 65, having APOEε4 had an effect on CTE severity equivalent to playing an additional seven years of football, meaning it more than doubled risk," says Mez.

According to the researchers, these findings provide insight into how CTE progresses, which may provide new targets for developing treatments to slow or stop CTE progression.