Traffic-Related Air Pollutants and Alzheimer's Disease: Risk, Susceptibility and Mechanisms in Women

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Project-1 is designed to investigate the contribution of traffic-related air pollution (TRAP) to the risk, susceptibility and mechanisms of Alzheimer’s disease (AD) and related dementias (ADRD) in a nationwide cohort of women from the Women’s Health Initiative (WHI) Memory Studies (WHIMS). ADRD affects more women than men, and increasing evidence indicates different risk factors by sex, pointing to the need to identify modifiable environmental factors separately for women and men. In the last two decades, compelling data have shown that exposure to outdoor air pollutants including TRAP is a novel environmental determinant of brain aging. Despite the strong evidence for TRAP-induced neurotoxicity (e.g., increased Aβ deposit shown in Project-3), human data on whether and how TRAP exposure effects brain aging remain limited and inconsistent. Previous studies had notable limitations: (1) lacking prospective evidence for an increased ADRD risk associated with TRAP; (2) not based on our current understanding of early cognitive change, biomarkers, and neurobiological classification of AD; (3) not studying AD risk resulting from TRAP effects before late life (e.g., aged < 55); and (4) providing limited insight on the brain structure and neuropathology linking TRAP to early cognitive deficits or an increased risk of AD. To address these knowledge gaps cost-efficiently, Project-1 builds on two well-characterized and geographically-diverse cohorts of mid-aged and older women in the WHIMS of Younger Women (WHIMS-Y; n=1346, inception age 50-54) and WHIMS-MRI (n=1403, inception age 65-80) followed annually since 1996, both with comparable longitudinal assessments on episodic memory and executive function. We further capitalize an NIEHS-funded R01 in WHIMS which employs sophisticated air pollution models developed by the MESA-Air ("Multi-Ethnic Study of Atherosclerosis and Air Pollution") team to estimate TRAP (NO2; PM2.5; exposure sources/components). Supported by the Core B1, we take the novel population neuroimaging approach to studying pathological brain aging in communities, drawing on both clinical and neuropathological classification of AD defined in very well-characterized samples from the Alzheimer’s Disease Neuroimaging Initiative with biomarkers of β-amyloid and neuronal injuries. State-of-the- art mediation and neurocomputational analyses will be conducted to examine the TRAP-affected brain structures and neuropathological pathways underlying the early cognitive deficits or MRI biomarkers of increased AD risk. Aim 1 will determine the impact of TRAP on early biomarkers predictive of increased risks for AD, mild cognitive impairment, and preclinical AD in older women. Aim 2 will examine the associations of cognitive decline reflecting early AD with TRAP exposure before/during late life. In Aim 3, we will take both targeted and agnostic approached with high-dimensional neurocomputation to elucidate the brain structure and neuropathology mediating the TRAP effects on pathological brain aging. Aim 4 will evaluate whether APOE4 and vascular brain injuries increase the susceptibility to the neurotoxic effects of TRAP exposure.