Substantial evidence indicates that exposure to outdoor air pollutants may accelerate cognitive aging. Emerging data from animal models also point to a possible increase in the risk of Alzheimer's disease (AD) and related dementias with exposure to traffic-related air pollutants (TRAP). Animal models of TRAP show strong evidence of neurotoxicity, but existing studies of neurotoxic effects of TRAP on human brain aging have important knowledge gaps: 1) little long-term address history data; 2) little data on exposure effects before late life; 3) limited data on cognition, particularly mild cognitive impairment (MCI) or AD; 4) limited neuroimaging measures; 5) no examination of potential confounding early-life factors: 6) studies of older adults mostly on women; and 7) need for better understanding of gene-environment interactions. Project 2, built on the NIA- funded longitudinal Vietnam Era Twin Study of Aging (VETSA; R01 AG018386 & AG022381), is ideal for addressing these gaps. It includes male twins ages 51-60 at VETSA 1 (n=1291) and 55-66 at VETSA 2 (n=1205). VETSA is a geographically-diverse cohort from 49 states, offering great variability in TRAP exposure. Subjects have 10-12 hours of neuropsychological, psychosocial, and health/medical data at each timepoint; 545 and 447 have structural magnetic resonance imaging (MRI) at VETSA 1 and 2, respectively. We will address gap #1 by collecting and geocoding residential history data back to 1993, and in conjunction with Environmental Exposures Core C, create cumulative indices of TRAP. We will then be able to directly address gaps 2-7. TRAP will be characterized by the estimated ambient levels of NO2 (a gaseous surrogate), elemental carbon (EC) component of PM2.5 (a marker of diesel exhaust particle), and predicted source profiles of PM2.5. The age of VETSA subjects is ideal for examining TRAP effects before late life. We examine the following aims: Aim 1. Assess TRAP effects on brain structure/function: Main effects. We predict TRAP exposure will be associated with higher AD-related brain signature scores, cerebral hypoperfusion (paralleling Mouse Project 4), and white matter hyperintensities. TRAP exposure will be associated with poorer cognitive function and greater cognitive decline over time. Aim 2. Assess the impact of TRAP on cognitive and brain aging: Mediation. We will examine associations between TRAP and specific measures of cognition with a focus on episodic memory, executive function, and processing speed, as well its mediation by specific brain measures. Diffusion tensor imaging (DTI) indices of brain microstructure have not been examined in prior studies. We will examine mean diffusivity in both grey and white matter in medial temporal and frontal regions. Aim 3. Examine gene-environment (GE) interaction. 3a) We hypothesize that adverse TRAP effects on brain and cognitive decline will differ as a function of APOE-ε4, and polygenic risk scores for AD, inflam...