ABSTRACT In response to RFA-OH-21-004, we explore the association between WTC exposure and cognitive decline via non-cognitive pathways of physical and mental health conditions, specifically abnormal spirometry and chronic PTSD. This project will answer critical questions relating to long-term effects of physical and mental health conditions, and further expand our knowledge on non-cognitive pathways that lead to cognitive decline. World Trade Center responders have been shown to experience rapid physical aging, poor mental health outcomes, and more recently, early onset of cognitive impairment. Early onset cognitive impairment may be operating via mechanisms that manifest as non-cognitive symptoms. Abnormal spirometry and chronic post- traumatic stress disorder (PTSD) are two highly prevalent and pervasive physical and mental health conditions in WTC responders that may be indicative of insidious cognitive decline. Indeed, it has been two decades since the September 11th terrorist attacks, and as this cohort moves into older age, disentangling specific pathways to cognitive decline will inform not only on preventative efforts but also on specialized interventions in high risk individuals. This project will use secondary data from the Stony Brook University World Trade Center Health Program (SBU WTC-HP, R01 AG049953). Aim 1 will test the hypothesis that the joint effects of abnormal spirometry and chronic PTSD on cognitive decline are larger than their individual effects. Aim 2 will then investigate the extent to which abnormal spirometry and chronic PTSD individually and conjointly mediate the association between WTC exposure and cognitive decline. Compelling previous work from our team supports this project: We have previously shown that cognitive function and physical function decline co-jointly; we have shown that respiratory symptoms and chronic PTSD in WTC responders co-occur frequently; and we have shown that chronic PTSD is in the pathway to early- onset cognitive impairment in WTC responders. These findings point towards a shared underlying mechanism affecting these conditions and outcomes; however, further investigation is needed to determine chronicity and paths from WTC exposure to cognitive decline. In this project, we will systemically examine the direct and indirect non-cognitive paths from WTC exposure to cognitive decline to improve identification of individuals who are on specific non-cognitive pathways to cognitive impairment. This will eventually lead to prevention efforts to mitigate preventable cognitive impairment by treating non-cognitive symptoms.