Does exposure to the pesticide DDT contribute to Alzheimer’s disease risk? And if so, how? Jason R. Richardson, Ph.D., professor of pharmaceutical sciences at NEOMED, has received a $2.5 million grant from the National Institute of Environmental Health Sciences at the National Institutes of Health that will allow his team to study the topic. The award will be made over a five-year period for the proposal titled “Mechanism of Gene Environment Interactions in Alzheimer’s Disease.”
“People focus on the genetic risk, even though only a fraction of Alzheimer’s disease—about 10 percent—is caused by single genes. This grant allows us to study whether an environmental toxin, the pesticide DDT, may contribute to a person’s risk of developing Alzheimer’s, particularly in those that may already be more susceptible based on their genetics,’’ says Dr. Richardson. “Learning this is important, because better understanding of the interactions between genetics and environment could help us in early identification of people at risk for the disease. This new understanding will also have important applications in the study of additional neurodegenerative diseases, such as Parkinson’s.’’
Dr. Richardson notes that the study is particularly relevant now, because people who were growing up or adults in the ‘50s and ‘60s, when DDT was heavily used in agriculture and to control diseases, are now reaching ages when they would be most likely to develop Alzheimer’s. Although banned in the early 1970s, DDT and its metabolites can persist in the environment and in our bodies for decades. It is also still used around the world, both legally and illegally. In recent Food Market Basket Surveys by the FDA, low levels of DDT were found in up to 27 percent of the food.
Talking about environmental toxins such as the organochlorine pesticide DDT is also relevant now, given current concerns about how to fight the Zika virus, says Dr. Richardson, who heads the Neurodegenerative Diseases and Aging research focus area at NEOMED. He notes that while DDT was finally banned in the U.S. by the Environmental Protection Agency in 1972, due to health concerns, it is still used in other countries, where it has been a lifesaving measure in battling malaria.
About the Research
In simplest terms, DDE is the residue of DDT. It remains in nearby soil and water for decades after DDT has been applied. It also lingers in people’s bodies. In earlier research, Dr. Richardson learned that people whose blood serum showed the highest levels of DDE were four times as likely to have been diagnosed with Alzheimer’s –a strong association. But it’s not enough for scientists to show association, notes Dr. Richardson. They also have to show whether is a mechanism for such an association.
The next discoveries were crucial, and potentially telling. Richardson’s group found that DDT and DDE increase levels of amyloid precursor protein (APP) in cells. When present in high levels, this protein can leads to the creation of the amyloid plaque found in Alzheimer’s disease. Those plaques (clusters of sticky proteins), along with neurofibrillary tangles in the brain’s cells, are associated with cell death and decline of cognitive function, such as learning and memory. Richardson believes that finding suggests a possible mechanism by which DDT exposure may contribute to AD.
Genetics appeared to be associated, too: People with a certain variant of a gene called APOE – known as APOE 4, to distinguish it from the variants 2 and 3—seemed to be more susceptible to the detrimental effects of DDE. Those with the APOE 4 gene and high DDE levels performed worse on a cognitive task than either those with just this genetic variation or high DDE levels. Hence, the next step.
In the new grant, Dr. Richardson’s team will use ‘’humanized mice,’’ in which mice APOE genes are replaced with human APOE genes in mouse models. Giving the mice cognitive tests and assessing brain pathology, they will test the idea that the degree to which a person is affected by DDE or DDT depends on their genetic predisposition.
The research will also involve personalized, patient-specific testing: what Dr. Richardson calls ‘’modeling the disease in a dish.’’ In one group of petri dishes, they will use cells from people with a ‘’normal’’ APOE3 gene. In another group, they will use cells with a ‘’bad’’ APOE4 gene variant. They will then expose each of them to DDT or DDE to see the effect, specifically, whether the APOE4 sample is more susceptible, similar to what they saw in people.
This represents a truly personalized approach to identifying those who might be at greater risk from exposures and determining the mechanism for the increased risk, says Dr. Richardson.
He notes, “Alzheimer’s disease has many contributing factors and each patient is different. Some die rapidly; others take a slow descent. Some have more severe mental issues (in addition to cognitive deficits) than others. There is no drug to treat Alzheimer’s; clinical trials have failed. So, if we can understand possible contributors to each person’s disease, be they genetic, environmental or a combination, perhaps we can either diagnose the disease earlier or tailor the treatment approaches based on that information.’’