The ALS/PDC syndrome of Guam and the cycad hypothesis

There is a high incidence on Guam of a severe tauopathy known as the Parkinson-dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.