Investigating the Causal Role of Particulate Matter Components on Lewy Body Dementia: Integrating Epidemiologic and Mechanistic Evidence - Project Summary As the United States population ages, the number of individuals affected by Lewy body dementia (LBD), characterized by hallmark α-synuclein (αS) pathology, is expected to rise. LBD, which profoundly impairs cognition, behavior, and mobility, currently affects 1.4 million individuals and their families in the United States. It is also the costliest dementia subtype to Medicare, with costs nearly double those of Alzheimer's disease. The growing health burden of LBD highlights the urgent need to identify and modify environmental factors that may contribute to its development. Increasing scientific evidence suggests that air pollution, particularly fine particulate matter (PM2.5), plays a significant role in the development and progression of αS-related dementia. Mechanistically, αS-related dementia may begin when foreign agents, such as PM2.5, enter the body via the nose or gut, triggering αS propagation in the brain and ultimately leading to dementia. Despite this, critical gaps remain in understanding the interaction between PM2.5 and LBD. Specifically, it is unknown which specific components of PM2.5 contribute to LBD via αS pathology. To address these gaps, we propose utilizing large-scale epidemiological data, advanced statistical methods, and mechanistic animal studies to identify which PM2.5 components associated with LBD diagnoses in human populations and investigate how they promote αS aggregation and prion-like spreading in vivo. We have assembled a multidisciplinary team of experts, including an atmospheric scientist, biostatistician, environmental epidemiologist, neurologist, and neuropathologist. The biostatistical and epidemiological experts will have access to 100% of the Medicare chronic condition data—including inpatient, outpatient, and prescriber claims data—from approximately 27 million Medicare enrollees in the United States from 2017 to 2022, where many LBD diagnoses are recorded. In parallel, the atmospheric chemistry and neuropathology experts will have access to laboratory resources for aerosol generation, atmospheric particle characterization, and a whole-body exposure (WBE) inhalation system to mimic ambient PM2.5 exposure to mice. The complementary expertise will enable us to examine the role of PM2.5 and its specific components in contributing to LBD. (1) We will evaluate the long-term effects of total PM2.5 exposure on LBD risk and establish an exposure-response relationship among Medicare enrollees. (2) We will quantify the effects of individual PM2.5 components and their mixtures on LBD risk using novel causal modeling approaches. (3) We will conduct in vivo studies using a WBE system in wildtype and αS-deficient mice to explore the causal mechanisms through which specific PM2.5 components, such as black carbon and nickel, induce αS pathology and neurodegeneration. By identifying the specific PM2.5 components most responsible for LBD risk and elucidating the biological pathways involved, our research will provide critical evidence to inform targeted air pollution policies and therapeutic strategies aimed at reducing the health burden of LBD in older populations.
