Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/−/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits

Associations Between Air Pollution Exposure and Empirically Derived Profiles of Cognitive Performance in Older Women

Background:Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective:We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter \u3c 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. Method:Women (N = 2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result:Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10–1.52) or superior attention (OR = 1.30; 95% CI = 1.10–1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17–1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67–0.97). Conclusion:Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains

Particulate Air Pollutants and Trajectories of Depressive Symptoms in Older Women

Objectives: Although several environmental factors contribute to the etiology of late-life depressive symptoms, the role of ambient air pollution has been understudied. Experimental data support the neurotoxicity of airborne particulate matter with aerodynamic diameter of ≤2.5 μm (PM2.5), but it remains unclear whether long-term exposure is associated with late-life depressive symptoms. Our secondary aim was to explore whether the observed associations between exposure and depressive symptoms are explained by dementia risk. Design, Setting, and Participants: Prospective community-dwelling cohort study from the Women's Health Initiative Study of Cognitive Aging (1999–2010). Our analyses included 1,989 older women (baseline age 73.3 ± 3.75) with no prior depression or cognitive impairment. Measurements: Participants completed annual assessments of depressive symptoms (15-item Geriatric Depression Scale). Average ambient PM2.5 exposure at the residential location was estimated by spatiotemporal modeling for the 3-years preceding each neuropsychological assessment. Participants underwent separate annual examinations for incident dementia defined by DSM-IV. Latent-class mixture models examined the association between PM2.5 and identified trajectories of symptoms. Results: Six trajectories of depressive symptoms were identified. Across all women, PM2.5 exposure was positively associated with depressive symptoms. The effect was especially strong in two clusters with sustained depressive symptoms (n = 625 sustained-mild [31%]; n = 125 sustained-moderate; [6%]). Among those with sustained-moderate symptoms, the estimated adverse effect of PM2.5 exposure was greater than that of hypertension. Among women without dementia, associations were modestly attenuated. Conclusion: Long-term exposure to ambient fine particles was associated with increased depressive symptoms among older women without prior depression or cognitive impairment

Association of Visual Impairment with Risk of Incident Dementia in a Women's Health Initiative Population

Importance: Dementia affects a large and growing population of older adults. Although past studies suggest an association between vision and cognitive impairment, there are limited data regarding longitudinal associations of vision with dementia. Objective: To evaluate associations between visual impairment and risk of cognitive impairment. Design, Setting, and Participants: A secondary analysis of a prospective longitudinal cohort study compared the likelihood of incident dementia or mild cognitive impairment (MCI) among women with and without baseline visual impairment using multivariable Cox proportional hazards regression models adjusting for characteristics of participants enrolled in Women's Health Initiative (WHI) ancillary studies. The participants comprised community-dwelling older women (age, 66-84 years) concurrently enrolled in WHI Sight Examination (enrollment 2000-2002) and WHI Memory Study (enrollment 1996-1998, ongoing). The study was conducted from 2000 to the present. Exposures: Objectively measured visual impairment at 3 thresholds (visual acuity worse than 20/40, 20/80, or 20/100) and self-reported visual impairment (determined using composite survey responses). Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for incident cognitive impairment after baseline eye examination were determined. Cognitive impairment (probable dementia or MCI) was based on cognitive testing, clinical assessment, and centralized review and adjudication. Models for (1) probable dementia, (2) MCI, and (3) probable dementia or MCI were evaluated. Results: A total of 1061 women (mean [SD] age, 73.8 [3.7] years) were identified; 206 of these women (19.4%) had self-reported visual impairment and 183 women (17.2%) had objective visual impairment. Forty-two women (4.0%) were ultimately classified with probable dementia and 28 women (2.6%) with MCI that did not progress to dementia. Mean post-eye examination follow-up was 3.8 (1.8) years (range, 0-7 years). Women with vs without baseline objective visual impairment were more likely to develop dementia. Greatest risk for dementia was among women with visual acuity of 20/100 or worse at baseline (HR, 5.66; 95% CI, 1.75-18.37), followed by 20/80 or worse (HR, 5.20; 95% CI, 1.94-13.95), and 20/40 or worse (HR, 2.14; 95% CI, 1.08-4.21). Findings were similar for risk of MCI, with the greatest risk among women with baseline visual acuity of 20/100 or worse (HR, 6.43; 95% CI, 1.66-24.85). Conclusions and Relevance: In secondary analysis of a prospective longitudinal cohort study of older women with formal vision and cognitive function testing, objective visual impairment appears to be associated with an increased risk of incident dementia. However, incident cases of dementia and the proportion of those with visual impairment were low. Research is needed to evaluate the effect of specific ophthalmic interventions on dementia.

Cognitive Function and Changes in Cognitive Function as Predictors of Incident Cardiovascular Disease: The Women's Health Initiative Memory Study

Background Cognitive impairment and decline may signal the increased risk of incident cardiovascular disease (CVD). We examined associations of global cognitive function, as measured by the Modified Mini-Mental State Examination (3MS) and changes in 3MS over time, with incident CVD, individual CVD outcomes, CVD death, and all-cause mortality. Methods A total of 5,596 women (≥ 60) from the Women's Health Initiative Memory Study free of CVD at baseline were followed for an average of 7.1 years. The 3MS was measured at baseline and annually thereafter. Cox proportional hazards regressions were used to model associations between baseline 3MS and changes in 3MS and time to events. Results In the fully-adjusted models for every 5-point lower baseline 3MS score, the risk was 12% greater for incident CVD, 37% for HF, 35% for CVD death, and 24% for all-cause mortality. No significant relationships were found for coronary heart disease (CHD), angina, stroke/transient ischemic attack (TIA), or coronary revascularization. When change in 3MS was added as a time-varying covariate in the fully-adjusted models, for every 1-point/year greater decline in 3MS, the risk was 4% greater for incident CVD, 10% for CHD, 9% for Stroke/TIA, 17% for CVD death, and 13% for all-cause mortality. Conclusions In older women free of prevalent CVD at baseline, lower baseline global cognitive function or decline in global cognitive function over time, increased risk of incident CVD, CVD death, and all-cause mortality

Ambient air pollution and long-term trajectories of episodic memory decline among older women in the whims-echo cohort

BACKGROUND: Episodic memory decline varies by age and underlying neuropathology. Whether ambient air pollution contributes to the heterogeneity of episodic memory decline in older populations remains unclear. OBJECTIVES: We estimated associations between air pollution exposures and episodic memory decline according to pollutant, exposure time window, age, and latent class subgroups defined by episodic memory trajectories. METHODS: Participants were from the Women’s Health Initiative Memory Study–Epidemiology of Cognitive Health Outcomes. Older women (n = 2,056; 74–92 years of age) completed annual (2008–2018) episodic memory assessments using the telephone-based California Verbal Learning Test (CVLT). We estimated 3-y average fine particulate matter [PM with an aerodynamic diameter of ≤2:5 lm (PM2:5)] and nitrogen dioxide (NO2 ) exposures at baseline and 10 y earlier (recent and remote exposures, respectively), using regionalized national universal kriging. Separate latent class mixed models were used to esti-mate associations between interquartile range increases in exposures and CVLT trajectories in women ≤80 and >80 years of age, adjusting for covariates. RESULTS: Two latent classes were identified for women ≤80 years of age (n = 828), “slow-decliners” {slope = − 0:12=y [95% confidence interval (CI): −0:23, −0:01] and “fast-decliners” [slope = − 1:79=y (95% CI: −2:08, −1:50)]}. In the slow-decliner class, but not the fast-decliner class, PM2:5 exposures were associated with a greater decline in CVLT scores over time, with a stronger association for recent vs. remote exposures [−0:16=y (95% CI: −2:08, −0:03) per 2:88 lg=m3 and −0:11=y (95% CI: −0:22, 0.01) per 3:27 lg=m3, respectively]. Among women ≥80 years of age (n = 1,128), the largest latent class comprised “steady-decliners” [slope = − 1:35=y (95% CI: −1:53, −1:17)], whereas the second class, “cognitively resilient”, had no decline in CVLT on average. PM2:5 was not associated with episodic memory decline in either class. A 6:25-ppb increase in recent NO2 was associated with nonsignificant acceleration of episodic memory decline in the ≤80-y-old fast-decliner class [−0:21=y (95% CI: −0:45, 0.04)], and in the >80-y-old cognitively resilient class [−0:10=y (95% CI: −0:24, 0.03)] and steady-decliner class [−0:11=y (95% CI: −0:27, 0.05)]. Associations with recent NO2 exposure in women >80 years of age were stronger and statistically significant when 267 women with incident probable dementia were excluded [e.g., −0:12=y (95% CI: −0:22, −0:02) for the cognitively resilient class]. In contrast with changes in CVLT over time, there were no associations between exposures and CVLT scores during follow-up in any subgroup. DISCUSSION: In a community-dwelling U.S. population of older women, associations between late-life exposure to ambient air pollution and episodic memory decline varied by age-related cognitive trajectories, exposure time windows, and pollutants

Adherence to a MIND-Like Dietary Pattern, Long-Term Exposure to Fine Particulate Matter Air Pollution, and MRI-Based Measures of Brain Volume: The Women’s Health Initiative Memory Study-MRI

BACKGROUND: Previous studies suggest that certain dietary patterns and constituents may be beneficial to brain health. Airborne exposures to fine particulate matter [particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5)] are neurotoxic, but the combined effects of dietary patterns and PM2.5 have not been investigated. OBJECTIVES: We examined whether previously reported association between PM2.5 exposure and lower white matter volume (WMV) differed between women whose usual diet during the last 3 months before baseline was more or less consistent with a Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND)-like diet, a dietary pattern that may slow neurodegenerative changes. METHODS: This study included 1,302 U.S. women who were 65-79 y old and free of dementia in the period 1996-1998 (baseline). In the period 2005-2006, structural brain magnetic resonance imaging (MRI) scans were performed to estimate normal-appearing brain volumes (excluding areas with evidence of small vessel ischemic disease). Baseline MIND diet scores were derived from a food frequency questionnaire. Three-year average PM2.5 exposure prior to MRI was estimated using geocoded participant addresses and a spatiotemporal model. RESULTS: Average total and temporal lobe WMVs were 0:74 cm3 [95% confidence interval (CI): 0.001, 1.48) and 0:19 cm3 (95% CI: 0.002, 0.37) higher, respectively, with each 0.5-point increase in the MIND score and were 4:16 cm3 (95% CI: -6:99, -1:33) and 1:46 cm3 (95% CI: -2:16, -0:76) lower, respectively, with each interquartile range (IQR) (IQR = 3:22 μg/m3) increase in PM2.5. The inverse association between PM2.5 per IQR and WMV was stronger (p-interaction <0:001) among women with MIND scores below the median (for total WMV, -12:47 cm3; 95% CI: −17:17, −7:78), but absent in women with scores above the median (0:16 cm3; 95% CI: −3:41, 3.72), with similar patterns for WMV in the frontal, parietal, and temporal lobes. For total cerebral and hippocampus brain volumes or WMV in the corpus callosum, the associations with PM2.5 were not significantly different for women with high MIND scores and women with low MIND scores

B vitamin intakes modify the association between particulate air pollutants and incidence of all-cause dementia: Findings from the Women's Health Initiative Memory Study

Introduction: Particulate air pollutants may induce neurotoxicity by increasing homocysteine levels, which can be lowered by high B vitamin intakes. Therefore, we examined whether intakes of three B vitamins (folate, B12, and B6) modified the association between PM2.5 exposure and incidence of all-cause dementia. Methods: This study included 7183 women aged 65 to 80 years at baseline. B vitamin intakes from diet and supplements were estimated by food frequency questionnaires at baseline. The 3-year average PM2.5 exposure was estimated using a spatiotemporal model. Results: During a mean follow-up of 9 years, 342 participants developed all-cause dementia. We found that residing in locations with PM2.5 exposure above the regulatory standard (12 μg/m3) was associated with a higher risk of dementia only among participants with lower intakes of these B vitamins. Discussion: This is the first study suggesting that the putative neurotoxicity of PM2.5 exposure may be attenuated by high B vitamin intakes

Erythrocyte omega-3 index, ambient fine particle exposure, and brain aging

OBJECTIVE: To examine whether long-chain omega-3 polyunsaturated fatty acid (LCn3PUFA) levels modify the potential neurotoxic effects of particle matter with diameters <2.5 µm (PM2.5) exposure on normal-appearing brain volumes among dementia-free elderly women. METHODS: A total of 1,315 women (age 65-80 years) free of dementia were enrolled in an observational study between 1996 and 1999 and underwent structural brain MRI in 2005 to 2006. According to prospectively collected and geocoded participant addresses, we used a spatiotemporal model to estimate the 3-year average PM2.5 exposure before the MRI. We examined the joint associations of baseline LCn3PUFAs in red blood cells (RBCs) and PM2.5 exposure with brain volumes in generalized linear models. RESULTS: After adjustment for potential confounders, participants with higher levels of RBC LCn3PUFA had significantly greater volumes of white matter and hippocampus. For each interquartile increment (2.02%) in omega-3 index, the average volume was 5.03 cm3 (p < 0.01) greater in the white matter and 0.08 cm3 (p = 0.03) greater in the hippocampus. The associations with RBC docosahexaenoic acid and eicosapentaenoic acid levels were similar. Higher LCn3PUFA attenuated the inverse associations between PM2.5 exposure and white matter volumes in the total brain and multimodal association areas (frontal, parietal, and temporal; all p for interaction <0.05), while the associations with other brain regions were not modified. Consistent results were found for dietary intakes of LCn3PUFAs and nonfried fish. CONCLUSIONS: Findings from this prospective cohort study among elderly women suggest that the benefits of LCn3PUFAs on brain aging may include the protection against potential adverse effects of air pollution on white matter volumes

Air quality improvement and cognitive decline in community-dwelling older women in the United States: A longitudinal cohort study

Background Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. Methods and findings We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = −0.42/year, 95% CI: −0.44, −0.40) and episodic memory (β = −0.59/year, 95% CI: −0.64, −0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. Conclusions In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging