PTSD, TBI May Affect Impact of APOE Gene Variant on Alzheimer Disease Risk

PTSD, TBI, and the APOE ε4 gene are strongly associated with the prevalence of ADRD among veterans.

Posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and the apolipoprotein E (APOE) ε4 gene, are associated with the risk for Alzheimer disease and related dementias (ADRD), according to study findings published in the journal Alzheimer’s & Dementia.

The US Department of Veterans Affairs’ (VA) Million Veteran Program (MVP) was launched in 2011. Veteran users of the Veterans Health Administration services volunteer to provide a blood sample for genetic analysis, consent to access of their VA electronic medical record (EMR), and complete a baseline survey on a broad range of demographic and health characteristics, including psychiatric disorders, medical history, and health risk.

Recognizing that it has long been suspected that AD–linked genetic variants may moderate the effects of adverse environmental factors conferring a risk for AD and vice versa, researchers sought to examine the prevalence of ADRD in veterans aged 65 years and older. Additionally, they estimated the effects of PTSD, TBI, and APOE ε4 on the risk for ADRD in veterans of European ancestry and veterans of African ancestry. Their theory was that PTSD and TBI would interact with genetic risk for AD and dementia, such that the ADRD risk associated with PTSD and TBI exposure would be greater in individuals with a higher genetic risk for AD.

[P]TSD and TBI history can be an important component of genetic dementia risk assessment and targeting early intervention, particularly in the veteran population.

The researchers examined APOE ε4 for interactions with PTSD and TBI. Then they evaluated whether interactive effects would be observed with AD risk conferred by other genetic loci by exploring the possibility of PTSD and TBI interactions with an AD polygenic risk score (PRS) that excluded the effect of APOE.

In the European ancestry cohort, a total of 11,112 patients with ADRD and 170,361 control individuals were evaluated. In the African ancestry cohort, a total of 1443 patients with ADRD and 16,191 control individuals were evaluated. The relative excess risk due to interaction (RERI) statistic was used to estimate addictive-scale interactions.

Based on addictive-scale interaction analyses, significant positive interactions were reported for 3 of the 4 models. In the European ancestry group, the RERI analysis demonstrated a significant APOE ε4 x PTSD interaction (RERI=1.28; 95% CI, 0.75-1.81) and APOE ε4 x TBI interaction (RERI=0.86; 95% CI, 0.48-1.24). In the African ancestry group, the RERI analysis revealed a significant APOE ε4 interaction with TBI (RERI=1.45; 95% CI, 0.15-2.75) but no significant PTSD interaction (RERI=0.37; 95% CI, –0.21 to 0.94). These addictive interactions show that the prevalence of ADRD associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles.

Several limitations of the study warrant mention. The researchers limited their research to late-onset dementia, based on the concern that cases of early-onset dementia may have a higher rate of false-positives than cases of late-onset dementia, especially among patients with TBI and/or pathophysiology. Since head injury may lower the onset rate of dementia, however, the findings from the study may not present the full effect of TBI-associated dementia. Furthermore, the findings are limited by the fact that history of TBI was based on self-report data from the MVP Baseline Survey, which was done to permit the inclusion of TBIs that may predate the VA EMR.

The researchers concluded that their findings suggest that “[P]TSD and TBI history can be an important component of genetic dementia risk assessment and targeting early intervention, particularly in the veteran population.”


Logue MW, Miller MW, Sherva R, et al; Million Veteran Program. Alzheimer’s disease and related dementias among aging veterans: examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury. Alzheimers Dement. Published online December 22, 2022. doi:10.1002/alz.12870