Alzheimer’s disease is now the sixth leading cause of death in the U.S., but researchers still do not know what causes the degenerative neurological disorder. In recent years they have pinpointed several genes that seem largely responsible for those cases in which the disorder develops early on, prior to age 60. They have also identified about 20 genes that can increase or decrease risk for the more common late-onset variety that starts appearing in people older than 60.



But genetics simply cannot explain the whole picture for the over five million Americans with late-onset Alzheimer’s. Whereas genetics contribute some risk of developing this version of the disorder, no combination of genes inevitably leads to the disease.



Scientists are now urgently searching for the other missing pieces to explain what causes late-onset Alzheimer’s. Some researchers have shifted their attention from genes to the environment—especially to certain toxins. Their studies of pesticides, food additives, air pollution and other problematic compounds are opening a new front in the battle against this devastating malady. Here’s a roundup of some of the possibilities being studied:



DDT (dichlorodiphenyltrichloroethane)

Scientists have already found a strong potential link between pesticides and Parkinson’s disease. Now, a preliminary study released in January suggests that the pesticide DDT, which degrades so slowly that it continues to linger in the environment more than 40 years after the U.S. Environmental Protection Agency banned its use in the U.S., may also contribute to Alzheimer’s.



Jason Richardson and his team at Rutgers University tested blood samples of people with and without late-onset Alzheimer’s. They found that most participants with the disease had levels of DDT and DDE (a metabolite of DDT) four times greater than the control group. Researchers also observed that participants with the most severe cases of Alzheimer’s had both a genetic predisposition and high pesticide blood levels, indicating that DDT/DDE may interact with genes to trigger the disease.



Richardson doesn’t have a definitive mechanism for how DDT exposure might lead to Alzheimer’s, however. But he speculates that DDT/DDE somehow encourage growth of the amyloid proteins that make up the plaques associated with the disease. He emphasized that his study is preliminary and his results will have to be replicated by future research on a larger scale.



In addition, some of the findings seem to contradict the study’s main conclusion. “The people I find most interesting are the ones who have really high levels of DDT and DDE, but don’t have Alzheimer’s,” Richardson says, “Maybe we’re a little early on those guys and they’ll ultimately end up with the disease. Or what would be more interesting is if their genetic makeup or lifestyle protects them from the disease.”



Nitrosamines

Another possible culprit for Alzheimer’s comes from the modern American diet. Researcher Suzanne de la Monte of Brown University’s Warren Alpert Medical School believes there is a connection between the rising number of Alzheimer’s cases and the greater amounts of nitrogen-based chemicals added to our food over the past few decades. Along with nitrogen-based fertilizers they include nitrates and nitrites, which are used to preserve, color and to flavor processed foods (as well as those added to tobacco products). In acidic environments, such as the stomach, or at high temperatures, as those reached in cooking, these compounds transform into toxic nitrosamines.



De la Monte’s study showed that nitrosamines damage cells’ energy-producing mitochondria and block insulin receptors in rats. Both of these factors, according to de la Monte, appear to cause neurological damage and encourage the development of insulin-related diseases, including diabetes, as well as cardiovascular disease and Alzheimer’s, in animal studies. Other research in humans also points to insulin resistance as a risk factor for Alzheimer’s. “All the diseases that have changed over the past forty or fifty years are related to insulin resistance and they track really nicely with changes in our food,” de la Monte says. “And nitrosamines, I tend to think they have a huge, huge role.” She is now searching for a biomarker that will allow her to measure nitrosamine exposure in people and see whether her study results translate from animals to humans.



Air pollution

Alzheimer’s researchers have also begun to subject air pollution to scrutiny. Soong Ho Kim reported in the journal F1000Research that mice rapidly developed Alzheimer’s amyloid plaques after exposure to aerosolized nickel nanoparticles, a component of air pollution. A 2004 study of thickly polluted Mexico City autopsied brain tissue of lifelong residents and found amyloid plaques and inflammation spread throughout their brains. Several studies have also found a possible link between dementia and particulate matter, a by-product of combustion already known to damage the cardiovascular system.



Air pollution does not just exist outdoors. In China, whose population is the world’s largest consumer of tobacco, researcher Ruoling Chen of King’s College London studied the effects of secondhand cigarette smoke on the country’s cognitive health. His research team assessed almost 6,000 people over age 60 in China’s cities and rural areas for their exposure to secondhand smoke. Chen reported in Alzheimer’s & Dementia that participants with the most severe dementia had been subjected to high levels of secondhand smoke. Chen interviewed people to assess their exposure, which is a standard study method but may be unreliable because participants may not accurately recall their exposure.



A difficult road ahead

Researchers acknowledge that it’s extremely difficult to discover links between environmental toxins and Alzheimer’s. Unlike DDT, most toxins do not persist in the body, which makes it hard for researchers to gauge a lifetime of exposure. If an environmental toxin does prove a risk factor, it will be only one part of a complex equation that includes genetics, lifestyle and possibly other environmental exposures that increase the chances of developing Alzheimer’s with age.



Alzheimer’s researchers have also been led astray in the past when they attempted to link environmental pollutants to the disease. In the 1970s and 1980s it was widely believed that aluminum caused Alzheimer’s because scientists discovered aluminum collected in amyloid plaques. But most researchers no longer accept this theory because subsequent studies showed that it was merely an innocuous coincidence that occurred due to the attraction between aluminum ions and amyloid plaques.



Richardson says that the claims about aluminum “likely poisoned the well” for later research on environmental factors. But this kind of research has become increasingly urgent as more people develop late-onset Alzheimer’s and no current treatment exists to prevent or even significantly delay to disease. According to Professor Steven DeKosky at the University of Virginia School of Medicine, it would make a huge difference if researchers found a way to even just postpone Alzheimer’s. “If you could delay onset of the disease by five years, you could cut down on about 50 percent of the cases,” DeKosky says. “If you could delay onset by 10 years, you could virtually wipe Alzheimer’s out because you’d have people live to the end of their lives without getting the disease.”