Scientists report that posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and the ε4 variant of the APOE gene showed strong associations with Alzheimer’s Disease and related dementias (ADRD) in a study of veterans led by Mark Logue, PhD, a statistician in the National Center for PTSD at the VA Boston Healthcare System. This work marked the first time that the medical community researched the simultaneous impact of PTSD, TBI, and genetic risk factors in a large cohort.

The researchers published their study “Alzheimer’s disease and related dementias among aging veterans: Examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury” in Alzheimer’s & Dementia.

With more than 40% of the Veteran population above the age of 75, the number at risk for Alzheimer’s and other forms of dementia is rising.

“This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic,” write the investigators.

“PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles.

“PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.”

At first, a greater percentage of ADRD in veterans with PTSD and in those with TBI was found, relative to those without, as well as higher rates of ADRD in veterans who had inherited the ε4 variant. Researchers then looked for interactions between the ε4 variant, PTSD, and TBI using a mathematical model. [Johnrob/Getty Images]
The researchers first found a greater percentage of ADRD in veterans with PTSD and in those with TBI, relative to those without, as well as higher rates of ADRD in veterans who had inherited the ε4 variant. Logue and his team then looked for interactions between the ε4 variant, PTSD, and TBI using a mathematical model.

The study found an increase in risk due to PTSD and TBI in veterans of European ancestry who inherited the ε4 variant. In veterans of African ancestry, the impact of PTSD didn’t vary as a function of ε4, but the TBI effect and interaction with ε4 was even stronger.  Other studies have suggested that ε4 may magnify the effects of a head injury and/or combat-related stress.

Capitalizing on the veteran’s program

The researchers carried out the study by accessing data from VA’s Million Veteran Program (MVP), one of the world’s largest databases of health and genetic information. MVP is aimed at learning how genes, lifestyle, and military exposures affect health and illness, with more than 900,000 Veterans enrolled in its climb to one million and beyond.

While large cohort studies have shown that PTSD and TBI increase the risk of dementia in veterans, Logue and his colleagues investigated further by studying these risk factors along with the APOE ε4 variant. Most people don’t inherit that variant, but those who do inherit it from one parent or both of their parents.

“Research has shown that if you inherit one copy of ε4, you’re at increased risk of Alzheimer’s disease,” he said, “and if you inherit two copies, you are at much higher risk.”

The number of ε4 variants a person inherits is fixed at birth, but their impact differs with age, according to Logue, who is also an army veteran and an associate professor at Boston University.

“The risk of Alzheimer’s disease increases with age for all of the APOE genotypes,” he said. “But when compared to people with two copies of the common variant, the difference in risk for those with a copy of ε4 appears to peak somewhere between age 65 and 70 and then decrease after that. Again, that doesn’t mean that your chances of Alzheimer’s decrease after that, just that the difference between the risk for those with and without ε4 diminishes.”

The study showed that the risk associated with PTSD and head injury was larger for ε4 carriers. Their model led the researchers to expect that for 80-year-old veterans of European ancestry who didn’t inherit the ε4 variant, the percentage of ADRD would be 6% greater for those with PTSD compared to those without.

But for 80-year-old veterans of European ancestry who inherited two copies of ε4, the percentage of ADRD would be 11% higher for those with PTSD than those without.

Clear link between PTSD, TBI on dementia risk a surprise

Logue was most surprised to see such clear evidence of a link between PTSD and head trauma on dementia risk.

“I’ve worked in Alzheimer’s disease genetics for over a decade now, and I was used to seeing a clear impact of APOE ε4 on Alzheimer’s risk,” he says. “However, in this cohort, the effects of PTSD and head injury were just as clear and looked similar to the effect of inheriting ε4 from one of your parents.”

Next, Logue and his colleagues would like to use MVP data to research other risk factors that are relevant to veterans, with the goal of learning how they may interact with Alzheimer’s risk variants. They are also looking to do genome-wide association scans to try to find new Alzheimer’s and dementia risk variants.

The most recent large-scale genome-wide association study of Alzheimer’s identified some 80 variants linked to the risk of Alzheimer’s, Logue said, noting that those variants were rare or had a much smaller impact than ε4.

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