Environmental Exposures and ADRD in the Health and Retirement Study Cohort

About This Grant

Alzheimer’s disease and related dementias (ADRD) are a growing public health burden and understanding modifiable ADRD causes is a national priority. Many classes of environmental chemicals, such as pesticides and per- and polyfluoroalkyl substances (PFASs) contain known neurotoxicants and are thus likely to contribute to ADRD risk, but we lack prospective data with appropriate temporality (exposures measured years before cognitive outcomes) in large and representative populations. Leveraging stored biospecimens from one of the largest, longitudinal, population-based United States cohorts, the Health and Retirement Study (HRS), we will generate a publicly available, prospective, environmental chemical resource, with exposure measures many years before the onset of ADRD or preclinical impairment. HRS participants are ages 50 and older and they have extensive existing biannual cognitive measures and ADRD fluid biomarker measures. Specifically, in Aim 1, we will perform new state-of-the-art non-targeted analysis in serum to measure chemical levels, including PFAS and pesticides, and test for association with cognitive function and decline, ADRD biomarker levels, and ADRD incidence. People are simultaneously exposed to pesticides, PFAS, and other chemicals in the neighborhoods where they live, work, play, and socialize. Social exposures, at the individual- and neighborhood-level contribute to stress and ADRD risk. Chemical and social exposure levels differ across US neighborhoods, with variation by geography and socioeconomic status. Therefore, in Aim 2, we will integrate mixtures of chemical and social exposures into the “exposome”, representing the totality of a person’s environment, when examining complex environmental contributors to ADRD. Additional evidence linking exposures and ADRD can be provided by intermediate molecular markers. These molecular intermediates may serve: 1) as biomarkers of exposure useful when direct exposure measures are not possible, 2) as mediators mechanistically linking exposure and ADRD, and 3) as connecting networks informing on overlapping pathways to deepen chemical and ADRD response understanding. In Aim 3, we will leverage existing measures of molecular intermediates, including DNA methylation, RNA expression, and immune cell profiles, with new measures of endogenous metabolomics and lipidomics, to assess molecular markers as exposure biomarkers or mediators to link exposures with incident cognitive status. Together, this project will identify individual chemicals, mixtures of chemicals, and their pathways that contribute to ADRD risk in a nationally representative sample, which will support ADRD prevention and intervention. Given widespread exposure levels to these environmental chemicals in the US, even modest associations with ADRD could represent a substantial number of preventable cases through individual- and population-level actions.