PROJECT SUMMARY: In the subsequent years following the World Trade Center (WTC) attack on September 11th, 2001, a cluster of chronic health conditions emerged among first responders (FRs) who were present during the aftermath of the attack. Many FRs were at Ground Zero for prolonged periods in the first week after the disaster, repeatedly exposing them to high levels of dust composed of particles of varying sizes that contained metals, polychlorinated biphenyls, polyaromatic hydrocarbons, among many known toxins. A growing body of scientific literature indicates that FRs who were exposed to high levels of dust for prolonged periods may have a greater incidence of mild cognitive impairment (MCI), as well as other neurological complications i.e. changes in white matter connectivity, decreased hippocampal volume which may put them at a greater risk of developing Alzheimer's disease (AD). Crucially, the risk relating to exposure was elevated in individuals carrying the AD vulnerability gene (i.e., apolipoprotein-E4 [APOE4], TREM2). Carrying a single APOE4 allele increases the risk for AD by approximately 4-fold, while double carriers have a 10-fold increased risk compared to the neutral APOE3 isoform. Based on this consideration, we have established the Late onset of Alzheimer's disease (LOAD)2 mouse model which carries a humanized ApoE knock-in mutation for the E4 isoform, a CRISPR/Cas9- generated APP allele with a humanized Aß1-42 region and R47H point mutation in the TREM2 gene to study the effects of WTC airborne PM and the role of age and genetic and environmental risk factors on LOAD. Additionally, in new studies, we found that the combination of experimental “extreme weather conditions” by heat stress (HS) in mice, primed by exposure to WTC airborne PM, exacerbates impairment in energy metabolism, altered lipid metabolism, and inflammatory responses. Consistent with this hypothesis, our feasibility evidence shows that the combination of environmental risk factors (such as HS) to a single WTC airborne PM exposure may negatively influence several metabolic cascades associated with energy metabolism. Based on this, our proposed study will define an age-dependent interaction regarding environmental “climate changes” (HS) to WTC airborne PM exposure on the onset and progression of LOAD. The overarching goal of this proposal is to examine the impact of WTC airborne PM on age x genetic interactions in response to exposure to WTC airborne PM and/or extreme weather conditions (HS), ultimately providing new strategies for risk assessment, risk reduction, and disease prevention in LOAD. The choice to study the role of WTC airborne PM in LOAD2 mice is fundamental to our understanding of age x genetic interactions in response to exposure to environmental stressors. The proposed studies seek to explicitly test the hypothesis that exposure to toxic WTC airborne PM causes long-term cognitive impairment and AD-type pathology by using rodent models. We understa...