Genetic link between PTSD and Alzheimer's debunked in veterans study

By Dr. Liji Thomas, MDApr 7 2024Reviewed by Benedette Cuffari, M.Sc.

Previous studies have suggested that combat veterans who develop post-traumatic stress disorder (PTSD) are at three to four times the risk for future dementia, which may be attributed to genetic risk factors. In a recent study published in Nature Mental Health, researchers identify shared genetic loci among military veterans with late-onset Alzheimer’s disease and related dementias (ADRD).

Study:  No replication of Alzheimer’s disease genetics as a moderator of the association between combat exposure and PTSD risk in 138,592 combat veterans. Image Credit: Prostock-studio / Shutterstock.com

The APOE gene

Specific variants of APOE, the gene that codes for apolipoprotein E (APOE), confer a substantial risk for Alzheimer’s disease (AD). For example, two copies of the E4 variant are associated with a 14-fold or more increased risk of AD among those of European ancestry and a three—to four-fold increased risk among those of African ancestry.

The APOE4 ε4 variant adversely affects the clearance of abnormal amyloid beta (Aβ) in the brain, which is the pathognomonic feature of AD. Other pathways affected by this gene include neuroplasticity, neuroinflammation, neurogenesis in the hippocampus, and glucose metabolism. The APOE4 variant also increases the risk of cardiovascular and metabolic disease.

Previous studies have reported an increased risk of dementia in APOE ε4 carriers who develop PTSD. These individuals also exhibit a more significant decline in cognitive performance with PTSD. PTSD may also be more common or more severe in APOE ε4 carriers after triggering exposures such as combat situations; however, evidence for this association is mixed and requires further research.

About the study

The current study examined the association between APOE variants and PTSD following combat exposure and head injury. The researchers also assessed the relationship between a polygenic risk score (PRS) for AD that did not include the APOE loci to identify possible non-APOE genetic risks common to both AD and PTSD.

Study participants were part of the United States Department of Veterans Affairs’ Million Veteran Program (MVP). All study participants were combat-deployed and represented individuals of both European (EUR) and African ancestries (AA).

The AA cohort was significantly lower in proportion to the EUR cohort. The subjects were further classified by age as young, middle-aged, and older. Each category had a relatively larger number of subjects than any earlier study.

Study findings

PTSD severity was strongly correlated with combat exposure. Middle-aged and older veterans were less likely to have PTSD; however, among younger veterans, the risk of PTSD increased with age.

The presence of the APOE ε4 variant did not affect PTSD severity, irrespective of ethnicity or age.

PTSD severity showed a rising trajectory in individuals with a history of head injury in all age groups. When combat exposure and head injury were considered, no correlation was observed with the APOE ε4 variant in moderating PTSD severity.

The AD PRS did not significantly affect PTSD severity nor interact with a head injury to affect PTSD severity risk. None of these factors could predict current PTSD risk.

Conclusions

The largest AD genetic risk factor, APOE ε4, does not increase risk for PTSD, either alone or in interaction with combat stress or head injury.”

Thus, earlier reports of interactions between the APOE ε4 variant and either PTSD diagnosis or severity may be attributed to non-generalizable sample-specific effects.

The lack of an interaction between the APOE ε4 variant and PTSD reflects the findings from previous large-scale genome-wide association studies (GWAS) of PTSD. This dismisses earlier theories that the APOE ε4 variant increases the risk for PTSD and, in later life, dementia.

The higher risk of ADRD in individuals with a history of PTSD cannot be attributed to genetic or biological factors that are shared between both conditions. Thus, although APOE variants that predict AD risk cannot be used to predict PTSD, the biological effects of chronic PTSD may be responsible for adverse effects on brain health.

Alternatively, PTSD may result in chronic stress, inflammation, and damage to the cardiovascular system and metabolic pathways, which may lead to neuronal oxidative stress and damage. These effects could be exacerbated by combat exposure and head injury, which increase the risk of both PTSD and AD.

A final hypothesis is that the correlation of PTSD is not with AD but with other dementias, which remains unobserved due to the rigor of current diagnostic processes. Thus, future studies are needed to explore these mechanisms to support the development of targeted interventions.

Simultaneously, AD needs to be more accurately defined for diagnostic purposes. By improving AD diagnostic strategies, other types of dementias may be studied for possible relationships with PTSD.