Prior studies have determined the Apolipoprotein-E (ApoE) ε4 allele presents a greater risk for developing Alzheimer's disease and for earlier onset of cognitive decline compared to individuals without the gene. Research has also recognized that traumatic brain injuries (TBIs) with loss of consciousness increase the risk for earlier development of the disease. This study sought to determine the moderating factor of TBI history on ApoE-ε4 risk associated with earlier Alzheimer's disease onset.

Participants included 9,585 individuals with autopsy confirmed Alzheimer's disease pathology, that had available ApoE genotype data, TBI data, and clinician determined age of cognitive decline, representing disease onset. A 2x3 factorial ANOVA was conducted to compare the main effects of ApoE-ε4 status and TBI history and the interaction effect between the two on disease onset. The analyses used three ApoE-ε4 groups and two TBI groups. The groups included: (1) no ApoE-ε4 allele; (2) one ApoE-ε4 allele; (3) two ApoE-ε4 alleles; (4) no TBI history, (5) positive TBI history.

Results indicated a significant interaction effect between ApoE-ε4 status and TBI history. Secondary analyses determined the driving force behind the interaction was the effect of ApoE-ε4, which had a significant impact on the age of onset in both TBI groups, while TBI history only significantly impacted onset in individuals without an ApoE-ε4 allele.

Contrary to prior research, these findings did not indicate TBI was significant in determining earlier onset. However, it is important to consider the large variability within the TBI group from the lack of differentiation between mild, moderate, and severe TBIs. Overall, these findings underline the greater risk and stronger impact that ApoE-ε4 poses for Alzheimer's disease onset compared to TBI. The results of this study emphasize the importance of evaluating ApoE-ε4 status for determining risk of earlier onset AD. Clinicians can better determine risk by considering patients' ApoE-ε4 status alongside TBI history.