You Are What You Breathe: Polluted Air Tied to Plaques, Brain Atrophy

Could air pollution even within Environmental Protection Agency limits—that is, not only in the world’s most polluted cities—hasten a person’s brain pathology and dementia? Yes indeed, according to two recent studies. In the November 30 JAMA Neurology, researchers led by Gil Rabinovici at the University of California, San Francisco, linked worse air pollution to higher brain amyloid burden in the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) cohort. In more than 18,000 cognitively impaired older adults from all over the U.S., the scientists compared brain amyloid plaque burden with concentrations of fine particulate matter (PM2.5) and of ground-level ozone. People who lived in an area with high PM2.5 levels had more plaques; ozone had no effect. A study in the November 18 Neurology led by Diana Younan, University of Southern California, Los Angeles, links air pollution to brain atrophy in 1,365 cognitively normal older participants in the Women’s Health Initiative Memory Study (WHIMS). The women who lived in areas of high PM2.5 had less gray matter in brain regions vulnerable to atrophy in Alzheimer’s disease. Taken together, these large cohorts add complementary evidence to a building consensus that toxic air may increase dementia risk.

  • PM2.5 linked to plaques, volume loss in Alzheimer’s brain areas.
  • No threshold effect; instead, a dose dependence dipping below EPA limit.
  • Atrophy progression seen in healthy, cognitively normal older women.

“We don’t know the mechanism of how air pollution increases dementia risk. Both these studies address that knowledge gap by indirectly measuring the effects of air pollution,” Eric Larson at the Kaiser Permanente Washington Health Research Institute, Seattle, told Alzforum. He mentioned that similar results from the Adult Changes in Thought (ACT) cohort are currently under review.

The plot of the air pollution-dementia story has been thickening. In the past decade, more and more studies have suggested that common air pollutants increase dementia incidence, and some have captured neurodegeneration with brain imaging (May 2020 news). The 2020 update to the Lancet Commission on Dementia Prevention, Intervention, and Care added late-life air pollution exposure as a modifiable risk factor for dementia, highlighting its growing recognition in dementia prevention (Aug 2020 conference news; Dementia Prevention, Intervention, and Care 2020). Just this week,  PM2.5 was linked to higher COVID-19 mortality (Wu et al., 2020). 

Tracking gray matter over time revealed that atrophy increases along with increasing air pollution exposure.

Fine particulate matter smaller than 2.5 microns, aka PM2.5., refers to particles  produced by construction sites, wildfires, car exhaust, and burning of various fuel sources (Inhalable Particulate Matter and Health). They can make their way into the brain to damage neurons and glia directly; or they can damage the brain vasculature, leading to dementia indirectly. Particulates and, shockingly, amyloid plaques, tau tangles, and α-synuclein aggregates have been reported in the brains of young people who live in Mexico City (May 2020 news). Alas, proof for a causative link between air pollution and dementia requires more studies linking exposure to intermediate steps in the disease’s decades-long pathogenic course.

In the JAMA Neurology paper, first author Leonardo Iaccarino looked at how air pollution affects amyloid plaque burden in cognitively impaired Medicare beneficiaries. Iaccarino and colleagues ran a secondary analysis of amyloid PET scans 18,178 participants had taken as part of the IDEAS study (Aug 2020 conference news). The scans were taken between February 2016 and January 2018, mean participant age was 76 years, 51.3 percent were women, 60.5 percent had mild cognitive impairment, and 39.5 percent had dementia.

The researchers recorded the air pollution levels in the ZIP codes where participants lived at two time points, one zero to two years before their scans, i.e. between 2015–2016, and another 13 to 15 years before their scans, between 2002–2003. Air pollution was measured as the predicted PM2.5, or ground-level ozone, levels recorded by the EPA using the so-called Downscaler model. This model combines atmospheric modeling with local air pollution measurements taken at specific times each day by local EPA monitors. This generates a geographic grid of daily mean PM2.5 and maximum ground-level ozone levels at the center of each U.S. Census block. The U.S. has more than 11 million census blocks but only about 42,000 ZIP codes.

Clearing Skies. Estimated air pollution where IDEAS study participants lived from 2002–2003 (left) and 2015–2016 (right) as mean daily PM2.5 levels. [Courtesy of Iaccarino et al., JAMA Neurology, 2020.]

Iaccarino and colleagues averaged PM2.5 and ozone levels during both time periods and matched them to each participant’s ZIP code. Ground-level ozone turned up no associations, but PM2.5 did. People who lived in areas with more PM2.5 were up to 1.15 times more likely to have a positive PET scan for every 4 μg/m3 increase in PM2.5 exposure. In other words, worse air quality increased risk of Aβ plaques. A participant’s sex or stage of dementia did not influence his or her risk of having a positive PET scan.

The average marginal effect indicated the same: For each 1 μg/m3 increase in PM2.5 exposure, a person had a 0.5 percent chance of having a positive PET scan in 2002–2003 and a 0.8 percent chance in 2015–2016. A dose-response relationship appeared, with people living in areas with the highest PM2.5 level having higher average marginal effects, up to 5 percent.

Melinda Power at George Washington University, Washington, D.C., cautioned that ZIP code-level associations are distinct from individual-level data. “Showing that people who live in a certain area have higher air pollution exposure and plaque burden is different than saying a person exposed to higher pollution is more likely to have more plaques,” she told Alzforum. “Area-level exposure may or may not be representative of individual-level exposure.” Iaccarino added that they are now collecting more information, including residential history and occupational exposure, to capture pollution exposure more accurately.

In the second study, Younan and colleagues looked at how air pollution related to brain atrophy in older women with normal cognition at baseline. For their longitudinal study, they identified 1,365 women aged 70–89 from the WHIMS Magnetic Resonance Imaging (WHIMS-MRI) cohort who had a brain MRI in 2005–2006. Of those, 712 had a second MRI in 2010–2011, with an average of 4.7 years between scans.

The researchers measured gray-matter volume in brain areas vulnerable to atrophy in AD, including the hippocampus, amygdala, and thalamus. They used the AD pattern similarity (AD-PS) score, which had previously identified gray-matter atrophy patterns unique to Alzheimer’s (Casanova et al., 2018). AD-specific atrophy was defined by scanning MRIs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A machine-learning algorithm compared the WHIMS-MRI and ADNI images, generating an AD-PS score based on how similar the gray-matter atrophy patterns of WHIMS participants were to the AD participants in ADNI.

Younan and colleagues collected every participant’s address at least twice a year, following participants throughout the six-year study. Younan used a spatiotemporal model to estimate daily PM2.5 levels based on EPA air-monitoring data at each of the participants’ addresses.

At the first MRI, average PM2.5 levels from the three previous years were not associated with gray-matter atrophy. However, tracking gray matter over time revealed greater atrophy with increasing air pollution exposure at the second MRI. For every 2.82 µg/m3 increment higher PM2.5 exposure, the women had greater gray-matter atrophy, equivalent to a 24 percent greater risk of developing AD over a five-year period. This held true after adjusting for demographic, lifestyle, and clinical characteristics, even in cognitively normal older women and in women without cardiovascular disease or risk factors. Chen’s lab had previously linked this PM2.5-mediated gray-matter atrophy to early memory decline (Younan et al., 2020). 

Both studies uncovered the same surprising result. The effects were seen even when air pollution was below the annual average limit of 12 μg/m3 set by the EPA in 2012 (Air Quality Standards for PM). Most other studies had seen increased dementia risk at far greater air pollution; only one other study had quantified dementia risk below the EPA limit, also finding increased risk (Grande et al., 2020). 

Air quality in the U.S. has been improving, especially since the 1990 amendments to the Clean Air Act (Particulate Matter (PM2.5) Trends). Even so, these data suggest pollution limits may need to be re-evaluated. “Optimistically, we can modify air pollution with public policies,” Larson said. Power agreed, adding that “improving air quality could have large impacts on many people without them individually modifying their behavior.”

Together, the papers link air pollution to Alzheimer’s dementia at two steps along its pathogenesis—Aβ accumulation and brain atrophy. “These studies converge on many points with two very different cohorts, different study designs, and different approaches to measure pollution exposure,” Iaccarino told Alzforum. Younan agreed: “Iaccarino captured a step earlier in the dementia pathway, showing that air pollution changes neuropathology that leads to brain structure alterations.”

Epidemiologists want to see the findings replicated. The evidence suggests that something is going on, but the signal linking air pollution to specific neuropathologies is not clear and compelling yet, Power said.

The scientists readily acknowledge their studies’ limitations. Iaccarino et al. lacked cognitively normal older adults because IDEAS was designed to generate clinical use evidence in hopes of persuading the Centers for Medicare and Medicaid Services to reimburse the cost of PET scans. Younan et al. lacked women under 65 because WHIMS was a clinical trial that was part of the Women’s Health Initiative. Both studies were secondary analyses of existing cohorts built for a different purpose, and hence were ill-equipped to detect other location-specific factors that worsen amyloid load or atrophy besides air pollution.

Caleb “Tuck” Finch, University of Southern California, Los Angeles, thought these were strong studies. He wondered what else could affect these outcomes. “Both studies mention that APOE4 increases vulnerability to air pollution but did not include APOE or other AD risk genes in their analysis,” he wrote to Alzforum. Finch has published extensively on the effects of air pollution on the developing, adult, and aging brain (e.g. Haghani et al., 2020; Haghani et al., 2020) Socio-economic factors are also tied up with both residential pollution and other health factors affecting dementia risk.—Chelsea Weidman Burke

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References

News Citations

  1. Air Pollution and Dementia—Through Hazy Data, Links Emerge
  2. Lancet Commission’s Dementia Hit List Adds Alcohol, Pollution, TBI
  3. The Air We Breathe—How Might Pollution Hurt the Brain?
  4. IDEAS Finds Small Drop in Hospitalizations, Missing Goal

Paper Citations

  1. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020 Aug 8;396(10248):413-446. Epub 2020 Jul 30 PubMed.
  2. Wu X, Nethery RC, Sabath MB, Braun D, Dominici F. Air pollution and COVID-19 mortality in the United States: Strengths and limitations of an ecological regression analysis. Sci Adv. 2020 Nov;6(45) Print 2020 Nov PubMed.
  3. Casanova R, Barnard RT, Gaussoin SA, Saldana S, Hayden KM, Manson JE, Wallace RB, Rapp SR, Resnick SM, Espeland MA, Chen JC, WHIMS-MRI Study Group and the Alzheimer's disease Neuroimaging Initiative. Using high-dimensional machine learning methods to estimate an anatomical risk factor for Alzheimer's disease across imaging databases. Neuroimage. 2018 Dec;183:401-411. Epub 2018 Aug 18 PubMed.
  4. Younan D, Petkus AJ, Widaman KF, Wang X, Casanova R, Espeland MA, Gatz M, Henderson VW, Manson JE, Rapp SR, Sachs BC, Serre ML, Gaussoin SA, Barnard R, Saldana S, Vizuete W, Beavers DP, Salinas JA, Chui HC, Resnick SM, Shumaker SA, Chen JC. Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease. Brain. 2020 Jan 1;143(1):289-302. PubMed.
  5. Grande G, Ljungman PL, Eneroth K, Bellander T, Rizzuto D. Association Between Cardiovascular Disease and Long-term Exposure to Air Pollution With the Risk of Dementia. JAMA Neurol. 2020 Jul 1;77(7):801-809. PubMed.
  6. Haghani A, Morgan TE, Forman HJ, Finch CE. Air Pollution Neurotoxicity in the Adult Brain: Emerging Concepts from Experimental Findings. J Alzheimers Dis. 2020;76(3):773-797. PubMed.

Other Citations

  1. Haghani et al., 2020

External Citations

  1. Inhalable Particulate Matter and Health
  2. Air Quality Standards for PM
  3. Particulate Matter (PM2.5) Trends

Further Reading

Papers

  1. Mir RH, Sawhney G, Pottoo FH, Mohi-Ud-Din R, Madishetti S, Jachak SM, Ahmed Z, Masoodi MH. Role of environmental pollutants in Alzheimer's disease: a review. Environ Sci Pollut Res Int. 2020 Dec;27(36):44724-44742. Epub 2020 Jul 27 PubMed.
  2. Fu P, Yung KK. Air Pollution and Alzheimer's Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2020;77(2):701-714. PubMed.
  3. Peters R, Ee N, Peters J, Booth A, Mudway I, Anstey KJ. Air Pollution and Dementia: A Systematic Review. J Alzheimers Dis. 2019 Feb 11; PubMed.
  4. Power MC, Adar SD, Yanosky JD, Weuve J. Exposure to air pollution as a potential contributor to cognitive function, cognitive decline, brain imaging, and dementia: A systematic review of epidemiologic research. Neurotoxicology. 2016 Sep;56:235-253. Epub 2016 Jun 18 PubMed.

Primary Papers

  1. Iaccarino L, La Joie R, Lesman-Segev OH, Lee E, Hanna L, Allen IE, Hillner BE, Siegel BA, Whitmer RA, Carrillo MC, Gatsonis C, Rabinovici GD. Association Between Ambient Air Pollution and Amyloid Positron Emission Tomography Positivity in Older Adults With Cognitive Impairment. JAMA Neurol. 2021 Feb 1;78(2):197-207. PubMed.
  2. Younan D, Wang X, Casanova R, Barnard R, Gaussoin SA, Saldana S, Petkus AJ, Beavers DP, Resnick SM, Manson JE, Serre ML, Vizuete W, Henderson VW, Sachs BC, Salinas JA, Gatz M, Espeland MA, Chui HC, Shumaker SA, Rapp SR, Chen JC, Women's Health Initiative. PM2.5 associated with gray matter atrophy reflecting increased Alzheimers risk in older women. Neurology. 2020 Nov 18; PubMed.

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