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Early Environmental Origins of Neurodegenerative Disease in Later Life

Parkinson disease (PD) and Alzheimer disease (AD), the two most common neurodegenerativedisorders in American adults, are of purely genetic origin in a minority of cases and appear in mostinstances to arise through interactions among genetic and environmental factors.

In this article wehypothesize that environmental exposures in early life may be of particular etiologic importance andreview evidence for the early environmental origins of neurodegeneration. For PD the first recognizedenvironmental cause, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was identified inepidemiologic studies of drug abusers.

Chemicals experimentally linked to PD include the insecticiderotenone and the herbicides paraquat and maneb; interaction has been observed between paraquatand maneb. In epidemiologic studies, manganese has been linked to parkinsonism. In dementia, leadis associated with increased risk in chronically exposed workers. Exposures of children in early life tolead, polychlorinated biphenyls, and methylmercury have been followed by persistent decrements inintelligence that may presage dementia.

To discover new environmental causes of AD and PD, andto characterize relevant gene–environment interactions, we recommend that a large, prospectivegenetic and epidemiologic study be undertaken that will follow thousands of children from conception(or before) to old age. Additional approaches to etiologic discovery include establishing incidenceregistries for AD and PD, conducting targeted investigations in high-risk populations, andimproving testing of the potential neurologic toxicity of chemicals.