A hallmark of Alzheimer’s Disease (AD) is regional brain “iron (Fe) overload”. We hypothesize that life- long exposure to inhaled Fe via air pollution (AP) is a contributor to elevated brain Fe and AD risk. In support of this hypothesis, AP has been linked to increased risk for AD with fine particulate matter (PM2.5) associated with increased risk for dementia, reduced memory, processing speed and increased cognitive impairment, PM2.5 exposures include ultrafine particles and metal contaminants. Of the many redox active metals/trace element pollutants in AP, Fe is often found at the highest concentrations. Studies examining Fe in frontal cortex of AD brains reported an abundant presence of magnetite (Fe2+/Fe3+ iron oxide) nanoparticles, consistent with an exogenous exposure rather than endogenous Fe source. It is critical to note that metal contaminants in AP are not borne equally by everyone. Low socioeconomic status (SES) communities show the highest AP and metal contamination levels (Fe - top percentiles ~0.135 µg/m3). In fact, neighborhood-level SES measures associate with memory and dementia risk. Further support for differential risk and the need to investigate inhaled Fe toxicity comes from the subway systems where Fe levels range 1000 x higher, from 141±81 to 329±116 µg/m3. These “ambient” and “subway” level concentrations provide the rationale for our experiments evaluating the link between inhaled Fe and neurodegenerative risk. Our preliminary data in mice demonstrates that inhaled Fe at “Subway” concentrations (~135 µg/m3) increases brain corpora amylacea, elevates phosphorylated tau protein levels, and results in female-specific hippocampal reductions and memory deficits. (AIM 1). We will evaluate whether AD-associated phenotypes arise at lower, closer to ambient Fe level exposures (1.35 µg/m3) and evaluate a time course of prodromal progression seen in AD studies, while differentiating between exogenous inhaled Fe from endogenous Fe. (AIM 2) Further escalating risk in these communities, poverty-related stress is characterized by a largely uncontrollable set of conditions, comprising a major risk factor for cognitive decline. Higher perceived stress is associated with increased risk for mild cognitive impairment, and two or more stressful life events increases risk for all-cause dementia. We predict that “ambient” Fe and deprived environments with uncontrollable stress exposures will result in AD neuropathology and memory loss, similar to higher “Subway” exposures. (AIM 3) We additionally predict that, conversely, enrichment with controllable stress will improve memory and ameliorate deficits associated with “Subway’ level Fe inhalation. These outcomes will derive from shared biological effects on oxidative stress and ferroptosis, with consequently increased neuroinflammation, reactive astrogliosis with white matter damage and neuronal loss. This research will inform public health policy and prevention to improve quality of life by mi...