Full length article Seeking environmental causes of neurodegenerative disease and envisioning primary prevention Peter S. Spencer a,b, *, Valerie S. Palmer a , Glen E. Kisby c a Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR, USA b Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA c Department of Basic Medical Sciences, Western University of Health Sciences, College of Osteopathic Medicine of the Pacific Northwest, Lebanon, OR, USA A R T I C L E I N F O Article history: Received 3 March 2016 Accepted 23 March 2016 Available online xxx Keywords: Western Pacific ALS-PDC Dementia Colon cancer Alzheimer disease Atypical parkinsonism Amyotrophic lateral sclerosis Gulf War veteran Guam, Kii Peninsula, West Papua Tauopathy Cycad b-N-methylamino-L-alanine Methylazoxymethanol A B S T R A C T Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinson- ism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer’s disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of disease-affected individuals and communities, the results of which can provide an invaluable guide to steer cogent epidemiological and laboratory-based research. ã 2016 Elsevier Inc. All rights reserved. “Health planners in developed countries are increasingly concerned with their burgeoning populations of elderly subjects and the consequent rising prevalence of age-associated disorders, notably those involving the nervous system. By the year 2050, current projections for the United States indicate that the proportion of the population aged 65 or over will be almost double (22%) the 1986 level, whereas the prevalence of senile dementia of the Alzheimer type will triple. It is thus entirely appropriate for the elderly of developed countries to be the subjects of intense scientific scrutiny aimed at understanding the causes and methods of prevention of the major neurodegenerative diseases that all too often accompany the second half of life. There are certain other parts of the world, however, notably in the western Pacific region, where such disorders are far more commonly encountered and where prospecting for etiology is more likely to be profitable. Indeed, one would posit that a knowledgeable extraterrestrial investigator, charged with the task of identifying causes of the great neurodegenerative diseases of Homo sapiens on planet Earth, would be unlikely to begin by researching elderly populations in Canberra, London, or New York; rather, the hunt for causation would probably commence in places such as Guam or Irian Jaya [West Papua] where, in certain spots, incidence rates for such diseases have exceeded worldwide * Corresponding author at: Department of Neurology, Oregon Health & Science University, HRC12D65, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201, USA. E-mail address: spencer@ohsu.edu (P.S. Spencer). http://dx.doi.org/10.1016/j.neuro.2016.03.017 0161-813X/ ã 2016 Elsevier Inc. All rights reserved. NeuroToxicology xxx (2015) xxx–xxx G Model NEUTOX 1966 No. of Pages 15 Please cite this article in press as: P.S. Spencer, et al., Seeking environmental causes of neurodegenerative disease and envisioning primary prevention, Neurotoxicology (2016), http://dx.doi.org/10.1016/j.neuro.2016.03.017 Contents lists available at ScienceDirect NeuroToxicology