Neurofibrillary tangle. Alzheimer disease
Credit: JOSE LUIS CALVO MARTIN & JOSE ENRIQUE GARCIA-MAURIÑO MUZQUIZ/Getty Images

Research by Mark Logue a statistician at the National Center for post-traumatic stress disorder (PTSD) at the VA Boston Health Care System, found a greater percentage of Alzheimer’s disease and related dementias (ADRD) in veterans with PTSD and in those with TBI (traumatic brain injury) who had inherited the ε4 variant, relative to those without it.

Full results of the study were published today in the journal Alzheimer’s and Dementia.The journal of the Alzheimer’s Association.

Among veterans of European ancestry, the data showed those with PTSD and TBI, with the ε4 variant were at greater risk relative to those without. 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 more pronounced.

“These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles,” the researchers 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 research was conducted using data from the Million Veterans Program (MVP), which has compiled genetic and health information on more than 900,000 veterans to date, with a goal of reaching a million, or more. The broad database is aimed at aiding research across a broad variety of health conditions, but Logue and his team noted that the ADRD research is especially important given the fact that more than 40% of all U.S. veterans are 75 and older.

While earlier studies among large cohorts have pointed to the increased risk of developing dementia among those with PTSD or who have experienced a TBI, the team for this new study sought to detail any additive risk of those with the APOE ε4 variant. The APOE ε4 is an inherited risk factor and people with the variant have inherited it from either one parent (one copy), or from both parents (two copies).

“The risk of Alzheimer’s disease increases with age for all of the APOE genotypes,” Logue 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.”

Using the data model developed in their research, the investigators estimated that for 80-year-old veterans of European ancestry who didn’t inherit the ε4 variant, the percentage of ADRD would be six percent 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.

A surprising result, Logue noted, was that this analysis provided 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 noted. “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.”

Logue and his team are now looking at number of different avenues for continued studies leveraging the MVP data to further identify factors contributing to Alzheimer’s disease risk. Previous research has identified as many as 80 variants associated with AD risk, though they confer a much smaller risk compared with APOE ε4. The investigators intend to conduct genome-wide research on the MVP data to look for even more risk variants, but note that including PTSD and TBI data will be vital in assessing veterans at risk.

“We know that genes play a large role in Alzheimer’s risk, but they don’t tell the whole story,” Logue said. “Right now, no genetic test can tell you if you’re certain to develop Alzheimer’s disease. Tests can only give an estimate of your likelihood of developing Alzheimer’s that may be higher or lower than average. Our study shows that these estimates will be more accurate if they incorporate more than just age and genetics. In veterans, a history of head injuries and PTSD can also make a large difference in dementia risk, so using that information will allow for more accurate measurement of the chances of developing dementia.”

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