Exposure to the herbicide Agent Orange has been tied to a significantly increased risk for dementia in Vietnam War veterans, new research shows.
Investigators at the University of California, San Francisco, found that veterans who had been exposed to Agent Orange had nearly a twofold increased risk of developing dementia compared to veterans who had not been exposed.
“This is important because the risk of dementia increases with age, and Vietnam veterans are now getting old enough to start developing dementia,” study investigator Deborah Barnes, PhD, MPH, University of California, San Francisco, and the San Francisco VA Health Care System, told Medscape Medical News.
The study was published online January 25 in JAMA Neurology.
Agent Orange is a powerful herbicide that contains the toxin dioxin. It was used during the Vietnam War by US forces to defoliate trees, shrubs, and crops that provided cover and food to opposition forces.
Exposure has previously been linked to neurologic disorders, including Parkinson’s disease, and metabolic disorders, including type 2 diabetes and systemic amyloidosis. The investigators note that the link between Agent Orange exposure and incident dementia diagnosis is unclear.
To investigate, the researchers analyzed Veterans Health Administration data on 316,351 veterans (mean age, 62 years), including 38,121 (12.1%) who were presumed to have been exposed to Agent Orange.
The prevalence of most conditions, including Parkinson’s disease, diabetes, and amyloidosis, was similar at baseline among veterans with and those without Agent Orange exposure.
After adjusting for demographic variables and comorbid conditions, veterans who had been exposed to the defoliant were nearly twice as likely as unexposed peers to be diagnosed with dementia during follow-up (5.0% vs 2.5%), with an adjusted hazard ratio of 1.68 (95% CI, 1.59 – 1.77).
In addition, veterans who were exposed to Agent Orange were about 15 months younger when they were diagnosed with dementia than unexposed veterans (mean age at dementia onset, 67.5 years vs 68.8 years).
Previous reports have found that Agent Orange exposure may be associated with increased risk for a variety of medical conditions, including some cancers, Parkinson disease, hypertension, and diabetes mellitus, Barnes said.
“This study does not show that the cause of dementia is related to Agent Orange, but further research should continue,” she told Medscape Medical News.
Commenting on the findings for Medscape Medical News, Paul Rosenberg, MD, Division of Geriatric Psychiatry and Neuropsychiatry, John Hopkins University School of Medicine, Baltimore, Maryland, said, “The methods are robust, and the study is very large,” and it does show a “meaningful increase” in dementia risk associated with Agent Orange exposure.
However, Rosenberg also noted that dementia risk is “notably affected by healthy lifestyle factors, including exercise, diet, stress management, involvement in cognitively stimulating activities, and sleep. None of these can be well assessed by these databases, and it is possible that veterans exposed to Agent Orange also have less healthy habits later in life.
“The mechanisms by which Agent Orange might affect dementia risk are really interesting,” Rosenberg said.
They include long-lasting stores of dioxin in fat, affecting diabetes risk; direct effects on pituitary hormones and neurotransmitters, including dopamine; and enhancement of oxidative stress. “The authors did an excellent job outlining these possibilities,” he added.
The association with Agent Orange is “particularly interesting because, in general, there aren’t many environmental exposures associated with any dementia except Parkinson’s,” Rosenberg said.
The take-home lesson, he said, is that veterans who were exposed to Agent Orange “should be extra vigilant about early signs of cognitive impairment” and should see their primary care clinician if they think they have them.
Also weighing in on the study for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific operations for the Alzheimer’s Association, noted that earlier data reported by Barnes and her colleagues at the 2019 Alzheimer’s Association International Conference found similar associations, “but a notably lesser effect size.”
“In that report, veterans with Agent Orange exposure documented in their health records were found to be 20% more likely to be diagnosed with dementia,” Snyder said.
Snyder said one limitation of the current study is that Agent Orange exposure is treated as a “yes/no consideration, whereas exposure level would have varied between individuals, depending on location, duties, and duration in Vietnam.
“It’s also important to note that the study population was 98% men, and all were Vietnam-era veterans. Therefore, these data aren’t generalizable to the general public and may only have implications for veterans who served in Vietnam and were exposed to Agent Orange,” said Snyder.
Echoing the authors, Synder cautioned that the study shows “an association and does not prove causation. More research is needed to understand the biological mechanisms that explain the relationship, if any, between Agent Orange and dementia risk,” she said.
The study was supported by the Department of Defense/Northern California Institute for Research and Education – The Veterans Health Research Institute. Barnes, Rosenberg, and Snyder have disclosed no relevant financial relationships.
JAMA Neurol. Published online January 25, 2021. Abstract