Project Summary The World Trade Center Environmental Health Center (WTC EHC) is a NIOSH-designated treatment and monitoring program for community members (“WTC Survivors”) with acute and/or chronic WTC exposures. Physical exposures include acute exposures to the massive dust clouds from the collapsing WTC buildings as well as chronic exposures to the resuspended dust and fumes in the subsequent months. Many also had traumatic psychological exposures as they witnessed death and dismemberment, worried about their own safety, lost their livelihood, or were displaced. There is a high prevalence of post-traumatic stress disorder (PTSD), chronic pulmonary disorder, and many types of cancers among WTC Survivors. Enrollees of WTC EHC include about 50% women and have diverse social-economic and racial/ethnic backgrounds. The WTC dust and fume exposures have been shown to be associated with mental-physical disorders, including PTSD, respiratory disorders, and cancers. Importantly, increased cognitive impairments have recently been extensively studied and widely reported for WTC responders; however, little is known for WTC Survivors. We hypothesize that the oxidative stress from the WTC exposures and affiliated systemic inflammation are part of the biological mechanism underlying the comorbid mental and physical disorders and contributing to neuroinflammation, neurodegeneration, and cognitive impairments in many WTC Survivors. To date, the biological mechanism underlying the WTC exposures, prevalent comorbid mental and physical disorders, and cognitive impairments and decline over time have not been investigated in WTC Survivors, leading to knowledge gaps and considerable uncertainty in both diagnosis and assessment of health disorders for Survivors. To improve diagnosis and treatment and to identify the biological underpinning of these health disorders, we propose a longitudinal study to assess cognitive functions and rate of changes over time among WTC Survivors enrolled at WTC EHC and also measure blood-based biomarkers of systemic inflammation, neuroinflammation, and neurodegeneration. We will conduct causal inference to analyze existing patient-level WTC exposures and comorbid mental-physical disorders data together with newly obtained cognitive scores and blood-based biomarker data to assess the effect of comorbid conditions and inflammation and neurodegeneration biomarkers in blood as mediators of the WTC exposures for cognitive impairments and cognitive decline over time both in the whole study population and in vulnerable subpopulations. The study aims to understand the biological mechanisms of how complex WTC exposures affect comorbid mental and physical disorders and impact cognitive dysfunctions in WTC Survivors. Completing this project may lead to the identification of novel blood-based biomarkers for non-invasive accurate disease diagnosis and cost- effective monitoring as well as potential targets for effective intervention.