Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 m (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimers disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimers disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimers disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Womens Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimers disease (Alzheimers disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17{micro}g/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy ({beta}PM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; {beta}NO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS ({beta}PM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 ({beta}NO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimers disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimers disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.