APOE Variant’s Impact on Alzheimer’s Disease Increased by Head Trauma, PTSD

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

Research by Mark Logue, a statistician at the National Post-Traumatic Stress Disorder (PTSD) Center at the VA Boston Health System, found higher rates of Alzheimer’s disease and related dementias (ADRD) in veterans with PTSD and those with TBI (traumatic brain injury) who have inherited the ε4 variant, compared to those without it.

The full results of the study were published today in the journal Alzheimer’s disease and dementia.Journal of the Alzheimer’s Association.

Among veterans of European descent, the data showed that those with PTSD and TBI, with the ε4 variant, were at greater risk compared to those without. In veterans of African descent, the effect of PTSD did not vary by ε4, but the effect of TBI and the interaction with ε4 was even more pronounced.

“These additive interactions indicate that the prevalence of PTSD-related ADRD and TBI increased with the number of inherited APOE ε4 alleles,” the researchers wrote. “A history of PTSD and TBI will be an important part of interpreting ADRD genetic testing results and making an accurate assessment of ADRD risk.”

The research was conducted using data from the Million Veterans Program (MVP), which has collected genetic and health information on more than 900,000 veterans to date, with the goal of reaching one million or more. The broad database is intended to help research a wide range of medical conditions, but Logue and his team noted that ADRD research is especially important given the fact that more than 40% of all US veterans are over 75 years old.

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

“Alzheimer’s risk increases with age for all APOE genotypes,” Logue said. “But 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 the ages of 65 and 70 and then decline thereafter.” Again, this doesn’t mean that your chances of getting Alzheimer’s disease decrease afterwards, just that the difference between the risk for those with and without ε4 decreases.

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Using a data model developed in their research, the researchers estimated that for 80-year-old veterans of European descent who did not inherit the ε4 variant, the rate of ADRD would be six percent higher for those with PTSD compared to those without. But for 80-year-old veterans of European descent who inherited two copies of ε4, the rate of ADRD would be 11% higher for those with PTSD than those without.

The surprising result, Logue noted, was that this analysis provided clear evidence of an association between PTSD and head trauma with dementia risk.

“I’ve been working on Alzheimer’s genetics for over a decade and I’m used to seeing a clear effect of APOE ε4 on Alzheimer’s risk,” he noted. “However, in this cohort, the effects of PTSD and head injury were equally clear and looked similar to the effect of inheriting ε4 from one of your parents.”

Logue and his team are now considering a number of different ways to continue their studies using the MVP data to further identify factors that contribute to the risk of Alzheimer’s disease. Previous research has identified as many as 80 variants associated with AD risk, although these confer a much lower risk compared to APOE ε4. The researchers intend to conduct a genome-wide study of the MVP data to look for even more risk variants, but note that the inclusion of PTSD and TBI data will be vital in assessing veterans at risk.

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

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