Abstract
Background Ambient air pollution exposures increase risk for Alzheimer’s disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results.
Method To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics.
Results On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43,-0.21]) and 0.12cm3 (95%CI=[-0.22,-0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29,-0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14,-0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy.
Conclusion In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.
Highlights
First longitudinal study on air pollution and medial temporal lobe (MTL) volume.
Late-life PM2.5 and NO2 associated with MTL atrophy over time in older women.
Heterogeneous adverse effects were observed across different subregions of the MTL.
Results not differ by APOE genotype, age, education, or cardiovascular risk factors.
Adverse effects remained at low-level exposure compliant with regulatory standards.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
The air pollution models were developed under a STAR research assistance agreement, No. RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage), awarded by the US Environmental Protection Agency (EPA). This study is supported by R01AG033078 (PI: Dr. Chen), RF1AG054068 (PI: Dr. Chen), R01ES025888 (PI: Drs. Chen & Kaufman), P01AG055367, the Southern California Environmental Health Sciences Center (5P30ES007048), and the Alzheimer's Disease Research Center at USC (NIA; P50AG005142 and P30AG066530). Dr. Salminen is support by grant 1R01ES033961-01, which is co-funded by NIEHS and NIA. Dr. Younan is also supported by a grant from the Alzheimer's Association (AARF-19-591356). Dr. Espeland receives funding from the Wake Forest Alzheimer's Disease Core Center (P30AG049638-01A1). Dr. Resnick is supported by the Intramural Research Program, National Institute on Aging, NIH. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Study protocols were approved by the Institutional Review Board at the University of Southern California. Written informed consent was obtained from all participants as part of the WHIMS-MRI study.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
Data, codebook, and analytic code used in this report are held by the NIH-funded Coordinating Center of the Women's Health Initiative at the Fred Hutchinson Cancer Research Center and may be accessed as described on the Women's Health Initiative website: https://www.whi.org/md/working-with-whi-data.