The rising prevalence of Alzheimer's disease and related dementias (ADRD) is a major public health and clinical challenge in the United States. Identification of ADRD causes to inform prevention and policy is the most efficient way to address these challenges. Most research to date has focused on identifying genetic causes of ADRD, however, recent population-scale studies have shown that environmental exposures, such as lead and cadmium, also contribute to ADRD risk and etiology. Initial findings on environmental factors linked to ADRD risk is promising, but human evidence is limited. A wide range of environmental exposures (exposome) have never been evaluated systematically in relation to incident ADRD. While there is a growing demand to predict future risk for ADRS more precisely, the role of exposomic data in improving ADRD risk prediction has never been evaluated. To address these gaps, we propose a prospective cohort study by capitalizing on existing large-scale, United States nationally representative, multi-ethnic population-based data. The National Health and Nutrition Examination Survey (NHANES, from 1998-2010, n>15,000) has a variety of environmental chemical exposure measurements, behavioral risk factors, and clinical phenotypes, and when linked to Medicare data, provides up to 25 years of incident ADRD.
We aim to (1) conduct a biologic hypothesis-based approach to test the associations of chronic exposure to lead and cadmium with incident ADRD; (2) conduct a data-driven environment-wide association study to systematically evaluate a wide-range of environmental toxicants with incident ADRD; and (3) develop and validate an exposome-based risk prediction model for ADRD using machine learning methods. The proposed study will advance scientific understanding on how modifiable and currently ubiquitous environmental neurotoxicants can lead to the development of ADRD. This study assesses the exposome to improve prediction of future disease risk and define vulnerable populations more precisely. This research will highlight individual-level and population-level interventions (i.e. precision health) to effectively prevent or reduce the risk of ADRD in the US population.
The proposed study is relevant to public health and precision health because comprehensive evaluation of a wide range of modifiable environmental exposures, including the currently ubiquitous environmental neurotoxicants lead and cadmium, will advance scientific understanding on the etiology of Alzheimer's disease and related dementias (ADRD) and inform individual-level and population-level interventions to effectively prevent or reduce the burden of ADRD. The proposed study is directly responsive to the 2018 National Institute on Aging AD Research Summit recommendations related to Understanding the Impact of the Environment to Advance Disease Prevention and Enabling Precision Medicine Research for AD/ADRD, and to the research goal of NOT-AG-18-053, Enabling precision medicine for AD/ADRD through deep molecular phenotyping.