US Researchers Identify Gene Variant That Increases Alzheimer's Symptoms

Researchers have identified a gene variant which increases the risk of post-traumatic stress disorder (PTSD) and head injury associated with Alzheimer's disease and related dementias (ADRD), according to a study. In a study of people at the US Department of Veterans Affairs (VA), US, researchers first found a greater percentage of ADRD in Veterans with PTSD and in those with traumatic brain injury (TBI), relative to those without. They also found higher rates of ADRD in Veterans who had inherited the e4 variant.

The findings appear in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The researchers then looked for interactions between the e4 variant, PTSD, and TBI using a mathematical model. Until now, the medical community has not researched the simultaneous impact of PTSD, TBI, and genetic risk factors in a large cohort.

The study, led by Dr. Mark Logue, a statistician in the National Center for PTSD at the Veterans Affairs (VA) Boston Healthcare System, found an increase in risk due to PTSD and TBI in Veterans of European ancestry who inherited the e4 variant. In Veterans of African ancestry, the impact of PTSD did not vary as a function of e4, but the TBI effect and interaction with e4 was even stronger. Other studies have suggested that e4 may magnify the effects of a head injury and/or combat-related stress, the study said.

"These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE e4 alleles," Logue and his colleagues wrote. "PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment." 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 1 million and beyond.

According to the study, with more than 40 per cent of the Veteran population above the age of 75, the number of former Service Members at risk for Alzheimer's and other forms of dementia is rising. 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 e4 variant. Most people do not inherit that variant, but those who do inherit it from one parent (one copy) or both of their parents (two copies), said the study.

"Research has shown that if you inherit one copy of e4, you're at increased risk of Alzheimer's disease, and if you inherit two copies, you are at much higher risk," he said. The number of e4 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, said the study. "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 e4 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 e4 diminishes," said Logue. The study showed that the risk associated with PTSD and head injury was larger for e4 carriers. Their model led the researchers to expect that for 80-year-old Veterans of European ancestry who did not inherit the e4 variant, the percentage of ADRD would be 6 percent greater for those with PTSD compared to those without. But for 80-year-old Veterans of European ancestry who inherited two copies of e4, the percentage of ADRD would be 11 percent higher for those with PTSD than those without.

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 e4 on Alzheimer's risk," he said. "However, in this cohort, the effects of PTSD and head injury were just as clear and looked similar to the effect of inheriting e4 from one of your parents."