Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is a unique neurodegenerative disease found on the island of Guam. This disease presents as a spectrum of neurological disorders characterized by features of ALS, parkinsonism, dementia, or a combination. The strongest epidemiological link has been to the consumption of the seeds from the cycad plant that purportedly contained a neurotoxin. Mice fed washed cycad flour show signs that mimic ALS-PDC, which include progressive deficits in motor, cognitive, and olfactory functions associated with neuron loss in the spinal cord, nigrostriatal system, cortex, hippocampus, and olfactory bulb. Through a series of chemical extractions of washed cycad flour, we identified steryl glycoside molecules as bioactive molecules that are neurotoxic in culture and in mice. A detailed review of this class of molecule revealed that the molecules are abundant in the environment, particularly in plants and bacteria. Lipid analysis showed that some bacteria that are associated with some forms of neurodegenerative disorders have the capacity to synthesize steryl glycosides. Furthermore, certain steryl glycosides have been found to be a cell stress mediator and may have some immunomodulary effects. We hypothesize that steryl glycosides are putative neurotoxins involved in the etiopathogenesis of several age-related neurodegenerative disorders. © 2006 Wiley-Liss, Inc.