J. William Langston, who has been studying and treating Parkinson’s disease for nearly 40 years, always has found it striking that so many more men than women show up in his clinic. His observation is not anecdotal. It is grounded in science and shared by many physicians: Men are roughly 1.5 times more likely than women to develop Parkinson’s, a progressive disorder of the nervous system that impairs movement and can erode mental acuity.

“It’s a big difference that is quite real,” says Langston, clinical professor of neurology, neuroscience and of pathology at the Stanford University School of Medicine and associate director of the Stanford Udall Center. “It’s pretty dramatic. I think anyone who sees a lot of Parkinson’s will tell you that.”

While the disproportionate impact is clear, the reasons for it are not. “It’s a great mystery,” Langston says. Researchers still don’t know what it is that makes men more susceptible to Parkinson’s, or what it is about women that may protect them — or both. But they are trying to find out.

“We in the research community have been working for decades to sort this out, but the answers are still elusive,” says Caroline Tanner, a neurology professor in the Weill Institute for Neurosciences at the University of California at San Francisco. “Nevertheless, it’s important to keep at it. We need to understand the mechanisms that underlie the specific differences between men and women so we can apply them to trying to prevent Parkinson’s.”

Parkinson’s results from the death of key neurons in the substantia nigra region of the brain that produce the chemical messenger dopamine. Over time, the loss of these nerve cells disrupts movement, diminishes cognition, and can cause other symptoms, such as slurred speech and depression.

Outward signs can include tremor, muscle rigidity, slowed motion, poor posture and balance, and the inability to perform unconscious actions, for example, blinking, smiling or arm swinging while walking. There is no cure, but certain medications and other treatments can ease the symptoms.

Scientists regard it as a disease of aging — most patients are older than 60 when diagnosed — although about 4 percent of cases occur among people younger than 50, one prominent example being the actor Michael J. Fox, whose symptoms began at age 29, and who established a Parkinson’s research foundation that bears his name. Nearly 1 million Americans are living with Parkinson’s, and about 60,000 new cases are diagnosed annually, according to the foundation.

Moreover, research indicates the incidence of Parkinson’s has been rising in recent years among both sexes, but more so among men, according to Rodolfo Savica, associate professor of neurology and epidemiology at Mayo Clinic. “Thirty years of observation showed an increasing number of cases, valid for both men and women, but much more evident in men,” Savica says of his study.

The phenomenon is not unlike certain other illnesses that afflict one sex more than the other, although in most cases it’s women who carry the greater burden. They suffer more autoimmune diseases, migraines, eye disorders and post-traumatic stress than men, for example, among other ailments.

It is well established that exposure to environmental toxins — pesticides and industrial solvents, for example — raises the likelihood of Parkinson’s, as well as aging, head trauma, and to a lesser extent, genetics. The latter, which often can significantly influence many diseases, seems to play only a minor role in Parkinson’s, except perhaps in early onset. “There are about 26 or 27 known genetic mutations in Parkinson’s, but they account for only a minority of cases, from 3 to 10 percent,” Savica says.

Moreover, researchers have found no genetic association with the sex disparity. “At the moment, there is no solid genetic basis for sex differences,” says Cornelis Blauwendraat, a staff scientist at the National Institute on Aging (NIA). “We and others have assessed this in fairly large studies, and the overall result was that there are no obvious genetic risk differences between males and females.”

Most experts believe it takes a combination of factors to prompt the disorder, both in men and women. “I see Parkinson’s as a multifactorial disease involving a number of variants,” Savica says. “Combine these with environmental exposures to one or more agents, and it causes the perfect storm.”

Confounding the picture is evidence that coffee drinking and smoking are protective against Parkinson’s, although experts don’t know why, and these habits don’t seem related to the gender gap, they say. They have not found evidence that women drink more coffee than men, or that women smoke more than men. While smoking by both men and women has declined dramatically in recent years, men still are more likely than women to be cigarette smokers, according to the Centers for Disease Control and Prevention.

Some researchers speculate that occupational hazards in jobs traditionally held by men might explain the difference. “The idea is that men are more likely to be in a workplace where they might be exposed to these chemicals,” Langston says.

Research suggests a relationship between Parkinson’s and agriculture, where herbicides and pesticides are used heavily, and industries that rely on solvents. Human studies have linked exposure to the herbicide paraquat and the pesticide rotenone to Parkinson’s, as well as to the industrial solvent trichloroethylene. (The use of many of these substances is now restricted, although not banned.)

“Parkinson’s disease is probably the neurodegenerative disease most influenced by the environment,” says Briana De Miranda, assistant professor of neurology at the University of Alabama at Birmingham, who studies the effects of chemicals on animals. “We know that exposure to certain chemicals leads to the development of Parkinson’s. We’ve seen people exposed to pesticides and solvents who have developed Parkinson’s.”

But when it comes to the sex differences, scientists point out that many men who develop Parkinson’s don’t hold these jobs, while some women do. Moreover, exposure to pesticides and other substances through food, well water and the release of industrial chemicals in communities doesn’t favor men over women.

“The vast majority of people are not exposed professionally, while we are all exposed through food and the environment,” says Alberto Ascherio, professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health, who studies how drugs, diet and lifestyle affect Parkinson’s risk. “But these exposures don’t differ between men and women, so that really can’t explain it.”

Tanner agrees. “There are lots of moving parts working together, and probably no single cause accounts for more men than women developing the disease,” she says. “While it’s true that many of these are traditionally male occupations, there is clearly more to it, and we just don’t know yet what it is.”

De Miranda has seen identical sex differences in rats she exposes to chemicals. One such study found more male rats develop Parkinson’s-like symptoms than female rats, even though both received the same level of contact with the insecticide rotenone. “Male animals are more at risk than female animals even if you give them the same exposures,” she says.

In a 2019 journal letter, Tanner described similar results in humans, that men working in agriculture bore a larger share of Parkinson’s compared with women who were similarly exposed. “This suggests there is something else in the biology, and biology is always complicated,” Tanner says.

Disease outcomes also differ between men and women. Studies show women tend to develop Parkinson’s later than men, have slower progression of the disease and respond more favorably to medication. “Generally women have a better prognosis than men,” Savica says.

Although some cognitive research has produced mixed results, one recent study found that men fared much worse than women, including in attention, processing speed, decision-making, memory and language, among others. “We found that men were more cognitively impaired than women across the board,” says Elizabeth Disbrow, associate professor of neurology and director of the Center for Brain Health at LSU Health Shreveport. “Their cognitive issues were much more pronounced.”

One of the tests, the Stroop, measures how quickly the brain can inhibit the influence of contradictory outside stimuli or interference when responding to a question. For example, the subject reads the word “blue” written in green ink and is asked to name the ink color. The test assesses how fast he or she can suppress the often initial impulse to say “blue,” and answer correctly.

“You have to inhibit learned behavior,” says Tyler Reekes, a doctoral candidate in LSU’s department of pharmacology, toxicology and neuroscience. “We give people a string of these, and we time how long it takes in order to measure their level of inhibition. We found that men with Parkinson’s disease had the worst performance compared to women with Parkinson’s, and controls of either sex who did not have Parkinson’s.”

Scientists don’t know why women seem to handle Parkinson’s better than men. One theory is that hormones protect them. Animal studies have found that estrogen deprivation destroys dopamine producing neurons. “There are estrogen receptors on the substantia nigra, so women with higher estrogens might be somewhat protected,” Langston says. “But it’s not proven — it’s a theory.” It’s also possible that estrogen may play a protective role in women before Parkinson’s symptoms appear, he says, since research suggests that the disorder can begin years before physical onset.

“Hormones are an interesting hypothesis, since, of course, there are clear differences in hormonal production between males and females,” says the NIA’s Blauwendraat. “However large-scale studies are lacking to link this to the male-female difference.”

Researchers also suggest that men have more alpha-synuclein than women, a protein abundant in the brain that has been implicated in the development of Parkinson’s and can be toxic when it “misfolds” into clumps known as Lewy bodies.

“Males have higher levels in the midbrain where dopamine neurons die off,” says Nathaniel Glassy, a research associate in LSU’s department of neurology and Center for Brain Health, and master’s degree student at the Harvard Extension School. “So, it may not only be that women have more reserve, but that men have a worse pathology with this protein.”

Experts agree that the male/female Parkinson’s puzzle will persist until researchers discover more information and can put all the pieces together. Among other things, Tanner would like to see scientists initiate a long-term prospective Parkinson’s study, much like the Framingham cardiovascular project. The Framingham study, launched in 1948, followed three generations and produced a wealth of information about heart disease.

Such a Parkinson’s study could do the same, she says.

“That’s what’s missing,” she says. “It’s a real paradox. Today we have better lab approaches and better computer programs capable of handling complex data sets, but we don’t have any good old-fashioned basic shoe leather epidemiology. We need to follow people over time, 30 or 40 years. This is a human disease. We should be looking at humans.”