Exposure to Particulate Air Pollution and Cognitive Decline in Older Women FREE

Despite the tremendous public health importance of cognitive decline and dementia in older age^1- 8 and much effort to develop effective preventive and treatment regimes, few modifiable risk factors have been identified.⁹ One model has forecasted that a broadly applied intervention that delays the onset of Alzheimer disease (AD) by 2 years could reduce the number of prevalent cases in the United States by approximately 2 million over a 40-year interval.⁷

Exposures to environmental toxins are potential risk factors that can be modified. Among the most pervasive environmental toxins is particulate air pollution. Extensive toxicologic and epidemiologic research has documented the relation of exposure to ambient particles with mortality and adverse respiratory and cardiovascular outcomes.^10- 11 Regulatory actions have reduced ambient particulate matter (PM), resulting in decreased mortality.^12- 13 However, reductions have not occurred uniformly,¹⁴ and health effects remain associated with PM, even at current levels.^15- 16

Very little is known about the role of PM exposure in relation to cognitive decline. Evidence supporting such a relation could implicate exposure reduction as a potential means for reducing the public health burden of cognitive impairment. Yet existing studies in humans are rare,^17- 22 few have used measures that account for the exposures' complex spatial and temporal patterns, and none has evaluated the cognitive effects of exposure to fine particulate air pollution (<2.5 μm in diameter [PM_2.5]). More notably, to our knowledge, no study has evaluated air pollution exposures in relation to longitudinal change in cognition. Therefore, using an established longitudinal study of older women living throughout the contiguous United States, we explored the hypothesis, specified a priori, that higher levels of exposure to PM would correspond to faster subsequent rates of decline in cognitive function.

The Nurses' Health Study (NHS) began in 1976 when 121 700 female registered nurses, aged 30 to 55 years and living in 11 US states, returned a mailed questionnaire about their medical history and health-related behaviors.²³ Since then, women have completed questionnaires every 2 years. To date, we have maintained follow-up of more than 90% of the original participants. This study was approved by the institutional review board of Brigham and Women's Hospital, Boston, Massachusetts.

From 1995 to 2001, we invited participants 70 years and older with no history of stroke to participate in a study of cognition. Of the 22 715 women who were eligible, we were unable to contact 1031 (4.5%). Of those remaining, 7.7% declined participation. Our analyses of exposure to coarse PM (2.5-10 μm in diameter [PM_2.5-10]) and PM_2.5 in relation to cognitive decline were based on data from up to 19 409 women with relevant data. Second (1997-2004) and third (2002-2008) cognitive assessments were administered a mean (SD) of 1.9 (0.4) years (n = 17 089) and 4.3 (0.8) years (n = 14204) after initial testing, reflecting at least 83% participation at each follow-up cycle.

We used geographic information system (GIS)-based spatiotemporal smoothing models to estimate exposures to PM₁₀ (<10 μm in diameter) and PM_2.5 for women residing in the contiguous United States. Coarse PM (PM_2.5-10) was the difference between PM₁₀ and PM_2.5. The methods for estimating these exposures for a 13-state region have been described previously.^24- 26 These methods have been extended to estimate PM₁₀ and PM_2.5 for the contiguous United States. Briefly, PM₁₀ and PM_2.5 monitor data were obtained from the US Environmental Protection Agency's (USEPA) Air Quality System (AQS).^26- 28 Monitor data on PM₁₀ were available nationwide from 1988 through 2007. Monitor data on PM_2.5 were not widely available before 1999. Thus, separate PM_2.5 models were developed for the pre-1999 and post-1999 periods, as in previous work.²⁶ The pre-1999 PM_2.5 model described seasonal spatial and monthly temporal patterns in the PM_2.5 to PM₁₀ ratio; we multiplied this ratio by PM₁₀ to obtain PM_2.5 predictions during this earlier period. Generalized additive mixed models were constructed to explain variation in measured PM₁₀ and PM_2.5 (post-1999) levels as the sum of effects of GIS-derived covariates (eg, distance to nearest road by road class, urban land use), meteorological data, and smooth spatial terms. These models were used with GIS-derived and meteorological data specific to each geocoded residential location for each nurse, to provide highly spatially resolved estimates of monthly PM₁₀ and PM_2.5 concentrations.

We averaged month-specific exposures to PM_2.5-10, PM_2.5, and PM₁₀ over several intervals preceding the initial cognitive interview: preceding month, year, 2 years, 5 years, and from 1988 through the preceding month. (See the eFigure and eAppendix 1 for further detail on PM exposure models and exposure estimation, and the timing of exposure and cognitive assessments.)

Cognitive testing was administered using validated telephone interviews. In the initial interviewing, we administered only the Telephone Interview for Cognitive Status (TICS)²⁹ and gradually added 5 more tests as high participation in the cognitive testing became apparent. Thus, the sample size differs somewhat across the cognitive tests, although participation rates remained identical for all tests. The TICS (n = 19 409) is modeled on the Mini-Mental State Examination (MMSE), and scores on the 2 tests are strongly correlated (Pearson correlation, 0.94).²⁹ A test of delayed recall of the 10-word list from the TICS (N = 16 908) was one of the 5 tests added to our battery. We also added the East Boston Memory Test (EBMT)^30- 31 to assess immediate (n = 18 662) and delayed ( = 18 635) paragraph recall. We administered a test of category fluency in which participants were asked to name as many animals as they could in 1 minute³² (n = 18 652). Finally, participants were administered the Digit Span Backward test³³ (n = 16 916), measuring working memory and attention. We used the full testing battery in the second and third assessment waves.

Our 2 prespecified primary outcomes were composite measures of cognition.^5,34 Specifically, to summarize the overall association of the air pollution exposure measures with cognitive performance, for women given all 6 tests (n = 16 887), we constructed a global score by averaging z scores from all tests. In addition, to assess overall verbal memory, a strong predictor of developing AD,³⁵ we combined the immediate and delayed recalls of the EBMT and the TICS 10-word list, for women given all 4 tests (n = 16 906), by averaging z scores from these tests. We extensively tested the reliability and validity of our telephone procedure for assessing cognition in high functioning, educated women (eAppendix 2).

We performed separate analyses for each of the PM measures, evaluating exposures in quintiles and as continuous variables, in relation to each cognitive score, including the verbal and global scores. All individual test scores were expressed as z scores, computed from the means and standard deviations in our study population. We compared trajectories in cognitive function over the 3 repeated measures across levels of the exposure measures, using generalized estimating equations regression models,³⁶ which allowed us to account for the correlations among repeated cognitive scores. In these models, we included terms for time, in years, since baseline cognitive assessment (as a continuous variable), air pollution exposure, and cross-products between the time and air pollution exposure terms. We adjusted these analyses for potential confounding variables, including age at cognitive assessment, education (registered nurse degree, bachelor's degree, or advanced graduate degree), husband's education (high school diploma or less, college degree, advanced graduate degree, or other), energy expended on recreational physical activity³⁷ (mean of responses to 4-7 questionnaires from 1986 through initial cognitive assessment, in quartiles), and alcohol consumption (mean of responses to 5-8 questionnaires from 1986 through initial cognitive assessment; none, up to 1 drink/wk, 2-6 drinks/wk, or ≥1 drink/d). We also included terms for the cross-products between each covariate and time. Additional adjustment for body mass index, diabetes, smoking (status and pack-years), aspirin use (3 frequency categories), and ibuprofen use (ever/never), did not change our findings. We conducted tests for linear trend across the PM quintiles using an ordinal variable that took on values corresponding to each quintile (1, 2, 3, 4, or 5).

All associations are reported as mean differences in cognitive score change over a 2-year interval, across exposure levels, as 2 years is the approximate interval between the testing cycles. In addition, to help interpret these mean differences, we compared findings on the relation of PM exposure to cognitive decline with age-related differences in cognitive decline, generated from the women in our data set. While our primary focus was on PM_2.5-10 and PM_2.5, we also evaluated PM₁₀.

In secondary analyses, we further adjusted our analyses for 3 measures of socioeconomic position in the census tract of residence: percentage of adults who have less than high school education, median home value, and median income. We also evaluated potential mediation of air pollution's association with cognitive decline by respiratory and cardiovascular conditions. In additional analyses, we further adjusted for self-reported emphysema and indicators of cardiovascular and cerebrovascular disease (high blood pressure, coronary heart disease, congestive heart failure, coronary artery bypass graft, transient ischemic attack, and carotid endarterectomy). Finally, we conducted sensitivity analyses restricted to women who did not move between 1988 and their first cognitive assessment (62% of the study population).

Estimated exposures to PM_2.5-10 and PM_2.5 varied widely among the women (Table 1). Estimated exposures over the month preceding the initial cognitive assessment were significantly correlated with longer-term exposures, but these correlations weakened with increasing measurement interval length (Table 1). For any given interval, estimated exposure to PM_2.5-10 was significantly correlated with estimated exposure to PM_2.5 but at magnitudes lower than the correlations between measures of the same PM type.

There were few meaningful differences in characteristics of women across quintiles of long-term PM_2.5-10 exposure (Table 2). From our multivariable-adjusted analyses, we observed rates of change in global cognitive function score that were significantly worse with higher levels of long-term exposure to PM_2.5-10 (P value for trend, .01; Table 3) and were significantly worse in the highest vs the lowest quintile of exposure (P = .003). Higher estimated PM_2.5-10 exposures in the 1, 2, and 5 years before the initial cognitive assessment were also associated with significantly worse subsequent decline on the global cognitive score. By contrast, exposure to PM_2.5-10 in the previous month was weakly and not significantly associated with cognitive decline. This pattern also was apparent in the findings for decline in the TICS and verbal memory scores, while short- and long-term PM_2.5-10 exposures were associated with comparable increases of rates of decline in digit span backward and verbal fluency scores.

The distributions of key characteristics across quintiles of estimated long-term PM_2.5 exposure were similar to those for PM_2.5-10 (Table 4), with few notable or consistent differences across quintiles. Similar to PM_2.5-10, women in the highest quintile of long-term exposure to PM_2.5 experienced significantly worse rates of change in the global score than did women in the lowest quintile (P = .03; Table 5). The trend of across quintiles were borderline significant (P value for trend, .11), but, when modeled as continuous variables, higher levels of both long-term PM_2.5 exposure (since 1988) and PM_2.5 exposure in the 5 years before the initial cognitive assessment were associated with significantly worse decline in global cognition. Decline in the individual cognitive domains generally was more strongly predicted by long-term than recent exposure to PM_2.5.

We observed similar differences in rates of global cognitive change per 10 μg/m³ increment in long-term exposure to PM_2.5-10 and PM_2.5 (−0.020 [95% CI, −0.032 to −0.008] and −0.018 [−0.035 to −0.002] standard units/2 years, respectively). These differences were similar to the difference in rates of change we observed between women in our data who were 1 to 2 years apart in age. Expressed per SD increment of each PM measure, these differences were −0.008 (95% CI, −0.013 to −0.003) and −0.006 (95% CI, −0.011 to −0.001) standard units/2 years.

Results from analyses of thoracic PM (PM₁₀) indicated generally faster rates of cognitive decline with higher level of long-term exposure (P value for trend, .<.001; eTable).

The associations of PM_2.5-10 and PM_2.5 with cognitive decline remained nearly identical when we adjusted our analyses for area socioeconomic position measures and for potential respiratory and cardiovascular intermediates. Analyses restricted to women who did not move yielded modestly stronger associations than those in our primary analyses. For example, 10-μg/m³ increments in long-term exposure to PM_2.5-10 and PM_2.5 corresponded to 2-year rates of decline in the global cognitive score that were worse by 0.025 (95% CI, −0.040 to −0.009) and 0.021 (95% CI, −0.043 to −0.000) standard units, respectively.

In this large, prospective study of older women, higher levels of long-term exposure to both PM_2.5-10 and PM_2.5 were associated with significantly faster cognitive decline. Placing these results in context, the differences in cognitive trajectory per 10-μg/m³ increment in long-term exposure to PM_2.5-10 and PM_2.5 were similar to the differences in trajectories between women in our study who were 1 to 2 years apart in age; that is, 10-μg/m³ higher exposure to PM was cognitively equivalent to aging by up to 2 years.

Several lines of indirect evidence indicate that PM may cause cognitive decline. Results from animal studies indicate that PM may access the brain either via circulation, or intranasally by direct translocation through the olfactory bulb.^38- 40 Once in the central nervous system, fine particles appear to exert adverse effects. Several animal studies have shown increased brain inflammation in response to air particulate exposures.^41- 44 In one experiment, mice were exposed either to filtered air, ambient ultrafine particles, or a mixture of fine and ultrafine particles sampled from Los Angeles, California, air. Two weeks after exposure, the brains of mice in both exposed groups contained higher levels of inflammatory markers, as compared with the mice in the control group.⁴¹ In dogs, signs of blood-brain barrier dysfunction, neural degeneration, cerebrovascular pathologic signs, and apoptosis in glial cells were present more often in those who had lived in Mexico City, Mexico, an area of high air pollution, than in dogs from less polluted cities.⁴⁴ In a postmortem study of 19 humans aged 34 to 83 years, who had died of nonneurologic causes, brain levels of cyclooxygenase-2, an inflammatory mediator, in the frontal cortex and hippocampus were higher among those who had lived in highly polluted cities than among those who had lived in less polluted cities. Importantly, brain levels of amyloid-β42, a pathologic hallmark of AD, were also higher among residents of the polluted cities.⁴⁵

The relation of PM exposure to cognitive decline may also be mediated through cardiovascular mechanisms. Extensive experimental and epidemiologic data indicate an association between exposure to air pollution and cardiovascular diseases and risk factors.^{10- 11,46- 47} This link is important because vascular factors have also been found to predict cognitive decline and dementia.^48- 49 In our data, however, adjustment for vascular factors did not change our findings, indicating that this is not likely a key pathway by which PM influences cognition.

Several limitations of our study warrant consideration. First, our estimates of PM exposure were indirect, based on spatiotemporal modeling of measurements from air pollution monitors located near each woman's residence. Measurement via personal air monitoring devices is not practical for long-term exposures in large-scale epidemiologic studies. Yet, exposure measurement errors in our study were likely to be nondifferential with respect to degree of cognitive decline, resulting in attenuated estimates of association. In addition, our PM exposure estimation^50- 51 features GIS-based spatiotemporal statistical models with little bias and high precision—particularly relative to other modeling approaches^24,26—accounting for small-scale variations in exposure at each participant's residential address using GIS-based covariates. This enabled us to assign estimated PM exposure levels to each address for each participant throughout the study period. Therefore, exposure estimates should be more accurate over time than estimates from initial addresses only. If chronic PM exposure particularly affects cognitive aging or if the biologic response occurs over longer than 1 month, this improved accuracy over time may explain, in part, why many associations corresponding to recent PM exposure were weaker than associations corresponding to long-term PM exposures, although it is also plausible that recent PM exposure is less biologically relevant.

It is possible that our results from this observational study are due to confounding. However, we did not find meaningful differences in numerous potential confounding variables across levels of PM exposure, and adjustment for a variety of known confounding variables—some of them measured repeatedly over several study cycles—did not eliminate the observed associations.

Although ours is the first study, to our knowledge, to investigate PM_2.5-10 and PM_2.5 in relation to cognitive aging, previous epidemiologic studies of adults generally suggest an adverse association between exposure to other forms of ambient particulates and cognition.^19- 22 In a study of 399 older women residing in urban and rural areas of Germany, residential proximity to busy road, a source of exposure to ultrafine particles, was associated with performance on several tests of cognition and olfaction, but higher PM₁₀ exposure in the previous 5 years was not.²⁰ Another study of 671 older men measured exposure to black carbon, a marker of traffic-related particles, and observed that higher level of exposure over the previous 1 to 11 years was associated with worse cognitive function.²² In the largest study to date, among 15 973 older adults in China, residents of areas with poorer air quality over the previous 7 to 10 years, measured by an index of ambient particulate and gas concentrations, were more likely to have poor cognitive function.²¹ Finally, in a study of 1764 adults aged 20 to 59 years living throughout the contiguous United States, higher exposure to ozone over the previous year was associated with worse performance on several cognitive and motor tests, but exposure to PM₁₀ was not. Neither of the 2 studies that examined PM₁₀ observed an association with cognitive function, yet the range of PM₁₀ exposure in the German study may have been too narrow (eg, 39.3-53.6 μg/m³ from 1980-1993) to observe a measureable effect,²⁰ and the 1-year measurement interval for PM₁₀ exposure used in the study of younger adults may have been too brief.¹⁹ These previous findings also suggest that traffic-related exposures may be important contributors to cognitive aging. Our findings complement and extend these previous findings not only by directly examining cognitive decline in a large population, but also by using detailed modeling of short- and long-term PM_2.5-10 and PM_2.5 exposures.

In conclusion, we found that higher levels of exposure to ambient PM are associated with worse cognitive decline. Importantly, these associations were present at levels of PM exposure typical in many areas of the United States. Therefore, if our findings are confirmed in other research, air pollution reduction is a potential means for reducing the future population burden of age-related cognitive decline, and eventually, dementia.