Genes really don’t tell the whole story. If you want to know your risk of Alzheimer’s, you need to think beyond “age and genetics” as found in a new study.

Although genetics have a substantial impact, they don’t fully explain why some people get Alzheimer’s disease and others don’t. There is currently no genetic test that can definitively determine whether or not you will develop Alzheimer’s disease.

Tests can only give you a rough idea of how likely it is that you will get Alzheimer’s, which could be higher or lower than average.

New research indicates that these predictions will be more accurate if we account for factors other than age and genetics.

According to the authors, this new study is the first to examine the combined effects of PTSD, TBI, and genetic risk factors on a large group of individuals

To date, PTSD, TBI, and genetic risk factors have never been studied together in a large cohort.

Dr. Mark Logue, a statistician at the VA Boston Healthcare System’s National Center for PTSD, oversaw a study of Veterans that found significant links between post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and the ε4 variant of the APOE gene, all of which are risk factors for Alzheimer’s disease and related dementias (ADRD).

The study’s first major finding was that Veterans who had inherited the ε4 variation were more likely to develop ADRD than their non-variant counterparts, as were Veterans with PTSD and TBI. After then, Logue and his colleagues used a mathematical model to search for any interactions that could exist between the ε4 variation, PTSD, and TBI.

The study found that Veterans with European roots who had the ε4 variant were more likely to have PTSD and TBI. The effect of PTSD on Veterans of African ancestry didn’t change as a function of ε4, but the effect of TBI and how it worked with ε4 was even stronger. Other studies have shown that ε4 may make the effects of a head injury or stress related to combat worse.

“These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles,” writes Logus. “PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.”

Tapping into the VA’s Million Veteran Program

The study was conducted using information from the VA’s Million Veteran Program (MVP), which is one of the biggest health and genetic datasets in the world. MVP tries to find out how genes, lifestyle, and exposures in the military affect health and illness. So far, more than 900,000 Veterans have signed up, and the number is expected to grow to 1 million and beyond.

More than 40% of Veterans are over the age of 75, making them a growing group at risk for Alzheimer’s disease and other kinds of dementia. Despite the fact that extensive cohort studies have shown that PTSD and TBI enhance the incidence of dementia in Veterans, Logue and his colleagues studied these risk variables in conjunction with the APOE ε4 mutation. Most people don’t get that variant from their parents, but those who do get it from either one parent (one copy) or both parents (two copies).

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

According to Logue, an associate professor at Boston University and a veteran of the United States Army, the influence of the number of ε4 variations a person inherits is different at different ages.

“The risk of Alzheimer’s disease increases with age for all of the APOE genotypes,” he points out. “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 results noted that ε4 carriers had a higher chance of having both PTSD and a head injury. Using their model, the researchers hypothesized that the proportion of ADRD would be 6% higher for those with PTSD compared to those without among Veterans of European ancestry aged 80 years old who did not inherit the ε4 variation. However, the probability of ADRD for 80-year-old Veterans of European ancestry who inherited two copies of ε4 would be 11% greater for those with PTSD than for those without.

PTSD, TBI increase dementia risk – a surprising link

Logue was most surprised to find such clear evidence that PTSD and head injuries increase the risk of dementia.

“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 adds. “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.”

Following that, Logue and his colleagues want to utilize MVP data to investigate additional risk variables important to Veterans, with the objective of understanding how they could interact with Alzheimer’s risk variations. Additionally, they want to conduct genome-wide association studies to hunt for fresh dementia and Alzheimer’s risk mutations. Logue said that the most recent large-scale genome-wide association study of Alzheimer’s found about 80 variants that were linked to the risk of Alzheimer’s. These variants were rare or had much less of an effect than ε4.

MVP data can be used to give this type of study more power, but the history of PTSD and TBI will be an important part of figuring out what the results of genetic testing for ADRD mean and doing accurate risk assessments for ADRD.

Results were published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association today.

Source: 10.1002/alz.12870

Image Credit: Getty