Interaction between APOE e4 and Age is Associated with Emotional Distress One Year after Moderate-Severe Traumatic Brain Injury

Emotional distress is common following moderate-severe traumatic brain injury (TBI) and is associated with poorer post-injury outcomes. Previously investigated sociodemographic, psychological, and injury-related factors account for only a small proportion of variance in post-TBI emotional distress, highlighting a need to consider other factors such as genetic factors. The apolipoprotein E gene (APOE) has been commonly studied in the TBI literature, with the e4 allele linked to worse neuronal repair and recovery. Few studies have investigated the potential relationship between APOE e4 and emotional distress after moderate-severe TBI, and results have been varied. We examined whether APOE e4 was associated with emotional distress 1 year following moderate-severe TBI, and whether this relationship was moderated by age, sex, and TBI severity (as indexed by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors provided saliva samples following inpatient admission to a TBI rehabilitation hospital. They completed a self-report measure of emotional distress, the Hospital Anxiety and Depression Scale (HADS), at a follow-up interview similar to 1 year post-injury. Complete genetic and follow-up data were available for 441 moderate-severe TBI survivors (mean age = 39.42 years; 75% male). We constructed a linear regression model that included APOE e4 carriage status (carrier vs. non-carrier) and interactions with age, sex, and TBI severity (APOE x age, APOE x sex, APOE x age x sex, and APOE x PTA duration) to predict total score on the HADS, while covarying for the main effects of age, sex, PTA duration, and previous head injury. There was a significant main effect of APOE e4, whereby e4 carriers reported less emotional distress than non-carriers (p = 0.04). However, we also found a significant interaction with age such that APOE e4 carriers reported increasingly greater emotional distress with older age compared with non-carriers (p = 0.01). A sensitivity analysis (n = 306) suggested that the APOE x age interaction, and main effects of age and previous head injury, were not unique to individuals with pre-injury mental health problems (n = 136). However, the main effect of APOE e4 was no longer significant when individuals with pre-injury mental health problems were removed. Our findings highlight the importance of considering moderation of genetic associations, suggesting that APOE e4 may be a risk factor for emotional distress specifically among older survivors of moderate-severe TBI. If these findings can be independently replicated, APOE e4 carriage status, interpreted in the context of age, could be incorporated into risk prediction models of emotional distress after moderate-severe TBI, enhancing targeted early detection and intervention efforts.