Pesticide Use and Markers of ADRD Neurodegeneration among US Farmers

Abstract Many pesticides are neurotoxic, and high exposures may have long-term neurodegenerative consequences. However, empirical evidence on the association between pesticides and Alzheimer’s disease and related dementias (ADRD) is preliminary and inconsistent. This project will identify links between pesticide exposure and markers across the ADRD neurodegeneration continuum, from preclinical biomarkers to clinical diagnosis. The study will be conducted among rural farmers, the group with particularly high pesticide exposure. The central hypothesis is that high pesticide exposure will increase the risk of ADRD neurodegeneration. This project will leverage 30 years of environmental health data from the Agricultural Health Study (AHS) with longitudinal cognitive assessments in an AHS sub-cohort - the Pesticides And Sense of Smell (PASS) Study. The central hypothesis will be tested by pursuing four specific aims: 1) identify pesticides that are associated with incident ADRD diagnosis using 30 years of comprehensive AHS cohort-wide Medicare-linkage data; and in the AHS- PASS sub-cohort, 2) identify the association between pesticide exposures and plasma biomarkers of ADRD; 3) determine the association of pesticide exposures with olfactory loss, a highly sensitive and easily assessable marker of early ADRD development, and 4) determine the association between pesticide exposures and cognitive decline and impairment. The AHS enrolled 52,394 U.S. farmers and is one of the world’s largest and best-characterized agricultural cohorts, with extensive longitudinal assessments of pesticide exposures over farmers’ prime working years. The ongoing PASS study further laid a solid foundation for leveraging the rich AHS environmental health data for ADRD research by establishing a sub-cohort of 2,545 AHS farmers with cognitive, olfaction, and motor assessments. The proposed research will involve longitudinally following PASS participants, collecting blood samples, and assessing olfaction, gustation, motor, and cognitive function over four time points. The study will be limited to PASS participants aged 50-79 at enrollment to target windows of preclinical and prodromal neurodegeneration when disease prevention is more feasible. The scientific rigor of this project is ensured by state-of-the-science pesticide exposure assessments in an occupationally exposed population, longitudinal outcome assessments across the ADRD continuum, carefully planned statistical analyses, and an experienced multidisciplinary and multi-institutional research team. Innovation and significance: This project will advance our knowledge of the association between pesticide exposures and ADRD by leveraging 30 years of extensive data from a well-characterized farming population. The project will bring new insights into the roles that a class of ubiquitous but poorly studied environmental exposures play in various stages of ADRD development, critically informing mechanistic research and preventive strategies. This project will also establish a unique ADRD research resource in rarely studied rural populations.