The Impact of Environmental factors on Lewy Body Dementia: Combining Claims Data and Mechanistic Studies - Project Summary/Abstract Lewy body dementia (LBD) is a neurodegenerative disorder affecting over one million Americans, second only to Alzheimer’s disease as a cause of neurodegenerative dementia. LBD is associated with abnormal deposits of α-synuclein (αSyn) in the brain. These deposits, called Lewy bodies, affect brain cell populations whose impairments, in turn, lead to problems with cognition, movement, and behavior. Older age and genetics are possible risk factors. Harmful environmental exposures may also increase the risk of LBD, yet their effects on LBD have generally been understudied. This proposal responds to PAR-24-249 and seeks to understand the interaction between environmental factors and LBD and its mechanisms. Our goal is to leverage massive nationwide claims datasets, coupled with advanced causal inference statistical methods reinforced by causal mechanistic studies in an in vitro LBD model system, to identify rigorously the modifiable environmental factors that contribute to LBD exacerbation and identify vulnerable subpopulations who may be at higher risk. We address this goal using Medicare claims where LBD is well identified through ICD codes. We have access to 100% Medicare Part A (inpatient hospitalizations) claims (>550k LBD hospitalizations over the study period) with longitudinally linked individual-level age, sex, race, cause-specific hospitalizations, and date of death for 2000- 2020, as well as 20% Part B (outpatient) and Part D (prescriptions) for a subset of years (2016-2018). We will link these data to daily (PM2.5, NO2, ozone) and annual (PM2.5, NO2, ozone, PM2.5 components (e.g. lead, iron, zinc), county level annual pesticides, daily weather variables, and area level factors (greenness, urban/rural, region, smoking). To mechanistically evaluate LBD susceptibility to environmental factors, we employ an SH- SY5Y model of LBD seeded with αSyn fibrils amplified from LBD patient-derived Lewy bodies that recapitulates phospho-S129-αSyn aggregates characteristic of LBD. Specifically, in Aim 1 we will quantify the association between individual and joint exposure to air pollution, metals, and pesticides and LBD exacerbation, evaluating both short-term (acute) and long-term (chronic) effects as well as identify vulnerable subpopulations. In Aim 2 we will evaluate toxicity and molecular mechanisms of PM2.5, metals, and pesticides in in vitro LBD models. And in Aim 3 we will quantify the association between temperature and temperature variability and LBD exacerbation as well as identify vulnerable subpopulations. In summary findings of this study will provide evidence on the causal link between environmental exposures and LBD exacerbation with the highest possible scientific rigor and will identify multiple modifiable risk and protective factors that lead to increased vulnerability in LBD. Completion of this project will provide the foundation to inform actionable policy (e.g., ensure stringent air pollution standards for PM2.5, implement heat prevention strategies, regulate use of certain pesticides) to help slow the LBD disease burden and improve the quality of life for millions of Americans.
