Island of the Mysterious Brain Disease

A half-century of research into one of the most intensely studied clusters of neurodegenerative disease in history has narrowed the cause to something in the environment that could damage the brains of people with susceptibility genes.

Immediately after World War II, U.S. Navy physicians stationed on the South Pacific island of Guam found a mysterious and devastating fatal brain disease among the indigenous Chamorro people. The symptoms--gradual paralysis, sometimes accompanied by the tremors of Parkinson's disease and the dementia of Alzheimer's disease--resembled several diseases of old age, but the disorder struck people as young as 20.

The crippling disease was once the leading cause of death on the island, killing one-quarter of adults in one village alone at its peak. In the 1950s, the incidence of this fatal paralysis, which is similar to that experienced by people with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), was estimated to be 50 to 100 times higher on Guam than at any other place on Earth.

Since it was discovered, researchers have been chasing after the cause of the syndrome, now called ALS/parkinsonism-dementia complex (ALS-PDC). Some scientists regard the baffling disease cluster as a neurological Rosetta stone that could hold the key to understanding the common neurodegenerative diseases. "Solve Guam, and you have the road map to solve all other gene and environmental interactions leading to neurodegenerative disease," says John Q. Trojanowski, director of the Alzheimer's Disease Center at the University of Pennsylvania School of Medicine in Philadelphia.

Over time, many suspected culprits have been investigated and dismissed, from genes and nerve toxins to microbes and minerals in the soil. Now several lines of research are converging on two factors: toxins from the island's ubiquitous palmlike cycad trees and genes that might somehow make the natives more susceptible to these compounds. Although the roots of the disease remain elusive--and the research findings remain inconclusive and sometimes controversial--scientists agree that the main take-home lesson from 50 years of research on Guam is that the evidence points to a strong environmental component—although no one knows what it is. Similar interactions between genes and the environment, they say, might be responsible for common neurodegenerative diseases everywhere.

In the search for an environmental explanation for ALS-PDC, one of the most recent theories fingers the flying fox, a local bat with a meter-wide wingspan that the Chamorros traditionally serve in coconut cream. Flying foxes eat cycad seeds, which contain a toxin that could damage human nerve cells. The Chamorros ate the local flying foxes nearly to extinction--perhaps unwittingly ingesting large amounts of the toxin.

Chamorros also eat cycad seeds, but they wash out the toxins before they grind the seeds into flour. Researchers have long suspected cycad seeds but have failed to prove that they cause the disease. Animal studies suggest that people would have to consume huge amounts of cycad flour to build up toxic concentrations of the compound, called BMAA. Flying foxes, however, might concentrate the toxin, like tuna fish concentrate mercury, says ethnobotanist Paul Alan Cox, director of the National Tropical Botanical Garden in Kalaheo, Hawaii, who proposed the idea 2 years ago in a paper co-authored by New York neurologist Oliver Sacks.

The BMAA theory remains speculative, and scientists are still scouting for chemical scapegoats. "Like any other plant, a cycad is a factory of chemicals," says neuroscientist Peter Spencer, director of the Center for Research of Occupational and Environmental Toxicology at Oregon Health & Science University. He and his colleagues are studying cycasin, another cycad neurotoxin that might slip through the body’s defenses disguised as a sugar molecule; it damages developing brains in young rodents.

Neuroscientist Christopher Shaw and his colleagues at the University of British Columbia in Vancouver 2 years ago discovered a novel set of cholesterol-like toxins in cycad seeds that cannot be washed out. Mice that are fed washed cycad chips acquire a progressive disease that resembles ALS-PDC. What's more, the brains of these mice show the biochemical changes that precede the formation of the characteristic protein tangles that choke the brain cells and spinal cords of Chamorros who have died from ALS-PDC.

The same mice might offer clues about the molecular mechanisms of the disease. Shaw's group recently reported that mice missing the apoE gene--which comes in versions associated with high, average, or low risk of Alzheimer's in people--stay healthier than normal mice fed a cycad diet. Perhaps the toxins are hitching a ride into nerve cells on the cholesterol-transport proteins made by apoE variants, says Shaw. Furthermore, mice with the high-risk version of the gene appear to develop symptoms earlier than do those with normal or protective forms.

Chamorros don't seem to have the risky form of the apoE gene. So researchers are still searching for genetic culprits. Trojanowski and his colleagues are looking at tau, a gene that is weakly linked to ALS-PDC in genetic studies. Mice with an overactive version of this gene, he finds, develop symptoms, and the pathological tangles, associated with the disease.

Although scientists don't yet have the answers, they have learned things from the Chamorros. Parkinson's disease, Alzheimer's disease, and ALS might be different forms of the same disease with similar pathology and causes, rather than distinct illnesses with independent origins, says Daniel Perl, director of neuropathology at Mount Sinai School of Medicine in New York City and a 20-year veteran of neuropathology studies on Guam.

"I'm not so sure that Guam holds the key to all neurodegenerative diseases," says Douglas Galasko, a neurologist at the University of California, San Diego, and head of an ongoing National Institute on Aging (NIA) project to investigate ALS-PDC in Guam. "But it's an important example about how environmental factors could contribute to neurodegenerative disease." If scientists can identify the toxin and the susceptibility genes and understand the mechanism for ALS-PDC on Guam, they could look for similar environment-gene interactions in more widespread neurodegenerative diseases, which might help prevent, detect, and treat such diseases, which are usually diagnosed too late for effective intervention.

For now, the mystery has no solution. Says gerontologist Ulla Craig, who has lived on the island for 25 years and directs the Guam arm of the NIA project: "We are so close, but we are still looking."

Carol Cruzan Morton is a freelance writer in Belmont, Massachusetts, who will cross off cycad seed flour and flying foxes from her shopping list even if the science is not yet definitive.