No replication of Alzheimer’s disease genetics as a moderator of the association between combat exposure and PTSD risk in 138,592 combat veterans

Large-scale cohort and epidemiological studies suggest that post-traumatic stress disorder (PTSD) confers risk for late-onset Alzheimer’s disease and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military veterans have reported that carriers of the apolipoprotein E (APOE) ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. Here we designed a cohort study to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD. To do so, we examined APOE ε4 and ε2 genotypes, an Alzheimer’s disease polygenic risk score, and other veteran-relevant risk factors for PTSD in age-stratified groups of individuals of European (n = 123,372) and African (n = 15,220) ancestry in the US Department of Veterans Affairs’ Million Veteran Program. Analyses revealed no significant main effect associations between the APOE ε4 (or ε2) genotype or the Alzheimer’s disease polygenic risk score on PTSD severity or diagnosis. There were also no significant interactions between measures of Alzheimer’s disease genetic risk and either combat exposure severity or history of head injury in association with PTSD in any age group. We conclude that the association between PTSD and the primary ADRD genetic risk factor, APOE ε4, that was reported previously was not replicable in this large and relevant dataset. Thus, the epidemiological association between PTSD and ADRD is not likely to be driven by the major genetic factors underlying ADRD risk. A study on a large cohort of military veterans of European and African ancestries finds no evidence that the APOE ε4 genotype moderates the impact of combat exposure on posttraumatic stress disorder symptom severity and diagnostic status.