Person-specific digitally measured air pollutant exposure and biomarkers of Alzheimer disease: findings from a pilot study

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METHODS: Fifty nine older participants underwent 7-day digital collection of exposure to PM and VOC by Atmotube Pro, a validated wearable air quality sensor. Person-specific levels of PM and VOC were correlated with biomarkers. RESULTS: The first functional principal components (FFPC) of PM and VOC captured 75% to 86% of the total variation, and were correlated with tau biomarkers (r=0.63, 0.60, and 0.60 between PM 1 , PM 2.5 , PM 10 and CSF total tau, respectively; p<5%). The FFPC of VOC was marginally correlated with amyloid biomarkers (r=-0.41 with CSF Aβ42/40, r=0.45 with CSF Aβ40, and r=0.25 with PET amyloid centiloid). DISCUSSION: Person-level air pollutant exposure is associated with AD biomarkers, but larger and longitudinal studies are needed. Alzheimer disease CSF biomarkers Imaging biomarkers particulate matter volatile organic compound Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. BACKGROUND Many environmental factors are associated with Alzheimer disease (AD) and related dementia (ADRD) 1-3 . In 2019 the World Health Organization (WHO) estimated that ~99% of the world population was living in regions where the levels of air pollutants exceeded the WHO air quality guidelines. Fine particulate matter (PM) is a mixture of solid particles and liquid droplets found in the air. Recent studies have found that higher exposure to the finest PM with diameters of 2.5 micrometers or smaller (called PM 2.5 ) was associated with lower concentrations of Aβ42 1 in cerebrospinal fluid (CSF), higher likelihood of a positive amyloid PET scan 2 , more amyloid plaques in autopsied brains 3 , and worse cognition with increased incidence of ADRD 4-5 . Higher levels of volatile organic compounds (VOC) were also found in AD patients compared with normal controls 6-7 . However, all existing research linking air pollutant exposure with AD biomarkers is based on regional, not person-specific, measurements of outdoor ambient air quality by government agencies (e.g., US Environmental Protection Agency [EPA] and European Environment Agency [EEA]). Because region-level measures of air pollutant exposure does not account for potentially large variability of outdoor air quality within regions or human factors due to mobility in daily life (e.g., time spent indoor vs. outdoor) 8 , the use of region-level measurements of PM exposure in associational analyses with person-level measurements of AD biomarkers may lead to significant statistical bias in the estimated effect size and loss of statistical power. The objectives of this pilot study were to obtain person-specific data on air pollutant exposure to PM and VOC, and to generate hypotheses about their associations with person-specific AD biomarkers. These biomarkers include the molecular imaging of amyloid and tau pathology with positron emission tomography (PET), plasma and cerebrospinal fluid (CSF) analytes 10-11 , brain volumes as measured by magnetic resonance imaging (MRI), and cognitive outcomes. 2. METHODS 2.1. Participants This study included older community-dwelling individuals recruited from the greater St. Louis, Missouri, metropolitan area and enrolled in the longitudinal studies of memory and aging at the Washington University (WU) Knight Alzheimer Disease Research Center (ADRC). Details of recruitment have been described 13-14 . Participants were predominantly cognitively normal at the time of the cross-sectional study, but some had early symptomatic AD (mild cognitive impairment, very mild dementia, or mild dementia with a typical AD dementia syndrome). Individuals were excluded if they had illnesses that could prevent participation in neuroimaging, or adversely affect cognition (e.g., metastatic cancer). The inclusion criteria for the current study were 1) availability of data of cognitive measures and AD biomarkers for at least one of the following biomarker modalities: plasma or CSF biomarkers; amyloid PET; structural MRI; and 2) normal cognition or early symptomatic AD. Potential participants meeting inclusion criteria were referred by Knight ADRC Clinical Core to the study, and then contacted by the study coordinator for their willingness to participate. All participants provided written informed consent at recruitment. The WU Human Research Protection Office approved procedures. 2.2. Demographics and social determinants of health Age, sex, years of education, and self-identified race were collected. Social determinants of health (SDOH) were assessed by a comprehensive battery that was recently developed at the Knight ADRC, referred to as the Social and Structural Determinants Influencing Aging and Dementia battery (SS-DIAD) 15 . 2.3. Clinical and cognitive assessments The Knight ADRC’s clinical and cognitive assessment protocols are consistent with that of the National Alzheimer Coordinating Center (NACC) Uniform Data Set (UDS) 16 . The NACC UDS includes standard diagnostic criteria for dementia and its differential diagnoses 17 , and uses the global Clinical Dementia Rating® (CDR®) 18 to operationalize the presence or absence of dementia, and when present, the severity of dementia. The UDS cognitive battery includes measures of episodic memory, working memory, semantic knowledge, executive function and attention, and visuospatial ability. All scales were oriented so that a larger score indicates better cognition. Z-scores were computed by subtracting the mean from the individual test scores and dividing the difference by the standard deviation (SD). A global cognitive composite score was constructed by averaging Z-scores across tests, as previously described 19 . 2.4. APOE genotypes Details of the APOE genotyping protocols have been described previously 20 . We dichotomized APOE ε 4 carrier status as positive or negative, indicating presence of one or two APOE ε 4 alleles, or none. 2.5. Digital collection of person-specific air pollutant exposure Digital measurements of person-specific air pollutant exposure were obtained by a commercially available and wearable air quality sensor, Atmotube Pro by Atmotube 21 . The device is designed with a carabiner so that it may be worn easily, and can be paired with a smartphone for pinging GPS coordinates ( Figure 1 ). Participants were asked to wear the device continuously for 7 days as they navigated their daily life. PM 1 , PM 2.5 , PM 10 , and VOC were measured about once every 5 minutes. Data were uploaded to the Cloud storage and then downloaded into our local secure servers for analyses after participants mailed their device back. Measurement properties of person-specific air pollutant exposure by Atmotube Pro have previously been established. Field and laboratory evaluations done by the South Coast Air Quality Monitoring District (AQMD) and its Air Quality-Sensor Performance Evaluation Center (AQ-SPEC) program 22 , an independent government agency, showed very strong correlations of PM 1 & PM 2.5 from Atmotube Pro sensors with EPA-approved Federal Equivalent Method (FEM) GRIMM in the laboratory evaluations (r > 0.99), and strong correlations with the same reference instrument in the field evaluation (0.79 <r²< 0.90; see the South Coast AQMD website). Test-retest reliability was provided in Section (Test-retest reliability of person-specific air pollutant exposure by Atmotube Pro) below. 2.6. CSF and plasma sample collection and analysis Blood was collected at the time of lumbar puncture (LP) or clinical assessment. CSF samples (20-30 mL) were collected at 8 AM after overnight fasting by gravity drip, briefly centrifuged at low speed, and aliquoted into polypropylene tubes prior to freezing at –80°C. All plasma samples (fasted and non-fasted) were analyzed at C 2 N Diagnostics with the PrecivityAD™ assay for Aβ42/40 and the PrecivityAD2™ for p-tau217, which has previously been described 23- 24 . An automated immunoassay (LUMIPULSE G1200, Fujirebio, Malverne, PA) was used to measure CSF concentrations of Aβ40, Aβ42, total tau (t-tau), p-tau181, and NfL 25-26 . Plasma NfL and GFAP were measured with Quanterix assay kits at WU on a HD-X analyzer 27-28 . 2.7. Brain imaging scan collection and processing The WU MRI protocol was implemented on 3T scanners for a total of approximately 60 minutes, and provided high gray-white matter contrast (1mm x 1mm x 1 mm) MPRAGE T1-weighted volume acquisitions 29 . PET PiB or Florbetapir (AV45) imaging and tau Flortaucipir (AV1451) imaging were conducted as detailed previously 29-30 . Structural MRI processing steps include motion correction, if applicable, averaging across scans, and atlas transformation. Regional volumes and cortical thickness were obtained via the FreeSurfer image analysis suite 31 . Determination of the regions-of-interest (ROIs) and pipelines were previously described 32 . FreeSurfer quality control (QC) criteria include (1) dural inclusion, gray matter exclusion, sulcus inclusion, cerebellum inclusion; (2) cerebellum, subcortical and hippocampus segmentation exclusion; (3) white matter exclusion, and (4) lateral ventricle segmentation. Analyses were performed on adjusted volumetric measures after regressing for the effect of scanner platforms and with adjustment for head size 32 . Amyloid and tau deposition in the ROIs was determined using FreeSurfer, and a standardized uptake value ratio (SUVR) with correction for partial volume effects was calculated 32 . The cerebellum was chosen as the reference region. The mean amyloid cortical SUVR was calculated from FreeSurfer regions within the prefrontal cortex, precuneus, and temporal cortex 29 . A centiloid scale to harmonize PET amyloid data from PiB and AV45 33 was developed, following the same level-2 calibration procedure in the original Centiloid Working Group paper 34 . Tau PET scans were collected and processed as previously described 12 . 2.8. Statistical analyses We first estimated the test-retest reliability of person-specific measurements of PM and VOC exposure over 7-days (i.e., the intraclass correlation coefficient (ICC)) 35 , using within-person consecutive measurements every 15 minutes. We then demonstrated that person-specific digital measurements of air pollutant exposure can capture between-individual variation in the same region and also within-individual variation in the same day by showing that participants from the same region do not share the same levels of PM exposure at the same time point, and that significant within-individual variation also existed across the 24 hours. We then conducted a simulation study to assess the potential bias and loss of statistical power when region-level measures of air pollutant exposure were used in the correlational analyses with AD biomarkers, in comparison to the person-specific measures. Finally, we analyzed 7-day air pollutant exposure data to PM and VOC by extracting main features from the time series, and then correlated these features with the available AD biomarkers. The first feature was the average daily exposure. The second feature was the proportion of time in 7 days that person-specific PM exposure levels were over the limit as recommended by the WHO (15 µg/m 3 for PM 1 and PM 2.5 , 45 µg/m 3 for PM 10 , and 0.05 ppm for VOC). The third feature was the first function principal component (FFPC) after performing a functional principal component analysis (FPCA) 36 of 7-day air pollutant exposure for each index. The association analysis was conducted to correlate each of the features from the 7-day air pollutant exposure with all AD biomarkers and cognitive outcomes that were obtained prior to the digital assessments of air pollutant exposure. Because not all participants had data on all biomarker modalities, each pairwise correlation with biomarkers and cognitive measures was estimated using the participants for whom the bivariate data were available. These pairwise correlations were tested for statistical significance by a standard normal test after the Fisher’s Z-transformation 37 . This test was chosen because Fisher’s Z-transformation can be approximated by a normal distribution regardless of the sample sizes, assuring the validity of our tests for a large number of pairwise correlations estimated from a wide range of sample sizes. Because of the preliminary nature of the pilot study with a primary goal to generate possible hypotheses for a future definite study, no rigorous multiplicity adjustment was performed. Estimates or correlations were adjusted for the effect of the time interval between digital collection of air pollutant exposure and AD biomarkers and cognition, and additionally adjusted for the effects other covariates: age, race, cognitive status, APOE ε4 status, years of education, sex, and medical comorbidities. Finally, after generating a set of hypotheses about the correlations between person-specific air pollutant exposure and AD biomarkers, we performed a power analysis to decide the sample sizes needed for future studies to rigorously test these hypotheses. 3. RESULTS A total of 59 individuals from the WU Knight ADRC participated in the pilot study. The participants had an average age of 76.28 y (SD=5.28y), an average of 16.29 (2.00) years of education, and were mostly female (58%) and predominantly White (85%) and cognitively normal (88%). About 39% of the participants were APOE Ɛ4 carriers. In addition to digital assessment of air pollutant exposure over 7 days, all 59 participants in our pilot study had NACC UDS 16 . A subset had data on CSF Aβ42/40, CSF total tau, p-tau181 (n=20) and multiple other CSF tau species (217,153,175, 205, 231, n=14) concentrations, plasma Aβ42/40 (n=54) and p-tau217 (n=22), cortical thickness and hippocampal volume (n=41), amyloid PET (n=35), and tau PET (n=33). Data collection of AD biomarkers and cognition occurred mostly prior to the data collection of air pollutant exposure, with a median time interval of between 0.9 y (cognition) and 5.9 y (CSF). Table 1 presents the basic demographics of the study participants. A total of 57 participants had data on CSF Aβ42/40 and/or amyloid PET, and 28 (49%) were amyloid positive by either CSF or PET amyloid measures. 3.1. Test-retest reliability of person-specific air pollutant exposure by Atmotube Pro From the 59 participants who underwent 7-day person-specific measurements of PM exposure, the within-persons consecutive measurements every 15 minutes were used to estimate the test-retest reliability of PM 1 , PM 2.5 , PM 10 , and VOC. Figure 2 presents the estimated intraclass correlation coefficient (ICC) as a function of time during a randomly selected day of 24 hours starting from midnight across participants, indicating very good test-retest reliability of the person-specific measurements of PMand VOC by the device. Not surprisingly, ICCs were lower around the earlymorning and lunch times, reflecting changes in the daily routine when air pollutant exposure was subject to sudden changes. 3.2. Person-specific digital measurements of air pollutant exposure captured between-individual variation in the same region and within-individual variation in the same day Among the 59 participants who underwent 7-day digital collection of their air pollutant exposure, eight from the same St. Louis region were measured on the same day (12/01/2023). Figure 3 presents the time course of PM 2.5 levels from the 8 participants from midnight to midnight, demonstrating that participants from the same region do not share the same levels of PM exposure at the same time point (as EPA’s region-level data would imply), and that significant within-individual variation existed across the 24 hours. 3.3. Statistical bias and loss of power when region-level measurements of air pollutant exposure were used in the correlational analyses with AD biomarkers To demonstrate the importance of person-specific measurements of air pollutant exposure, we simulated 5000 independent data sets to assess the statistical bias and loss of statistical power when a region-level PM exposure was correlated with a person-level AD biomarker. Each data set was originally simulated at the person level for both the PM exposure and biomarker over 100 participants from a bivariate normal distribution with a true correlation of 0.15 or 0.45. We then created the region-level PM exposure for a randomly selected subset of 100p% (0<p<1) participants, using the mean of the simulated person-specific exposures in the subset. Finally, we estimated the correlation between the PM exposure and biomarker and tested its statistical significance. Figure 4 shows the mean bias (defined as the mean of the estimates minus the true correlation) of 5000 estimated correlations (left vertical axis; red color) from the true correlations (0.15= solid line, 0.45=dashed line) and mean loss of statistical power of 5000 tests (right vertical axis; green color) from the true powers, as functions of p, the proportion of subjects with only region-level data of PM exposure, demonstrating increasing bias and loss of statistical power as p increases. Note that, when person-level data were used in PM exposure, i.e., p=0, no bias (=0, left vertical axis) and no loss of statistical power (=0, right vertical axis) were observed. 3.4. Correlation of person-specific exposure to PM and VOC with AD biomarkers The estimated Spearman correlations of person-specific daily PM 1 , PM 2.5 , and PM 10 exposure (averaged over 7 days) with CSF p-tau181 and total tau showed a strong statistical trend and ranged from 0.35 to 0.59. PM 10 exposure was also correlated with CSF p-tau153 (r=0.82, p=0.044) and showed a trend with the tau PET burden (r=0.22) and plasma p-tau217 (r=0.17). There was also a trend towards statistical significance in the correlation of VOC exposure with plasma p-tau217 (r=0.51, p=0.052), p-tau181 (r=0.41, p=0.134), and CSF p-tau217 (r=0.69, p=0.089). The estimated correlation of person-specific daily VOC level was -0.37 (p=0.210) with CSF Aβ42/40, -0.34 (p=0.019) with plasma Aβ42, -0.16 (p=0.278) with plasma Aβ42/40, and 0.20 (p=0.3) with amyloid PET centiloid. The FFPC derived from a functional principal component analysis (FPCA) 36 of 7-day air pollutant exposure for each index captured most of the variation across subjects (86.49%, 86.28%, 86.11%, and 74.80% for PM 1 , PM 2.5 , PM 10 and VOC, respectively), and may be interpreted as person-specific ‘total exposure’. The correlation matrix ( Table 2 ) showed positive correlations of the FFPC for both PM and VOC with almost all tau biomarkers, and some were statistically significant (r=0.63, 0.60, and 0.60 between PM 1 , PM 2.5 , PM 10 and CSF total tau, p<5%). The FFPC for VOC was marginally correlated with amyloid biomarkers (r=-0.41 with CSF Aβ42/40, 0.45 with CSF Aβ40, and 0.25 with PET amyloid). No correlations of air pollutant exposure were found with cognitive composite. 3.5. Correlations of person-specific time exposed to PM levels over WHO’s recommended limit correlated with AD biomarkers Using WHO’s recommended limits for daily PMand VOC exposure, we computed the proportion of time over 7 days that person-specific PM exposure levels were over the limit for each participant. Times of excessive exposure to PM 1 , PM 2.5 , and PM 10 were all significantly correlated with CSF total tau (r=0.85, 0.82, and 0.72, p=0.0002, 0.0005, and 0.006, respectively), and showed a statistical trend with CSF p-tau181 (r=0.36, 0.38, and 0.31, respectively). Time of excessive exposure to VOC was also marginally correlated with CSF Aβ42 (r=-0.2), plasma NfL (r=0.25) and cortical thickness (r=-0.18). 3.6. Correlation of person-specific exposure to PM and VOC with SDOH Although not significant, we found a statistical trend indicating that people who reported living in very littered neighborhoods were exposed to higher levels of PM 10 (r=0.24, p=0.131), and those feeling a strong sense of belonging to their neighborhoods were exposed to less VOC (r=-0.34 with the FFPC, p=0.03). 3.7. Sample sizes needed in a future study to power the test of the observed correlations Due to small sample size in our pilot study, very few of these correlations reported above were statistically significant after adjusting for multiple comparisons. However, multiple AD biomarkers had correlations with pollutants in the same direction (great biomarker abnormality was associated with higher levels of pollutants), suggesting a relationship between AD and pollution. More specifically, the statistical trends and relatively large magnitude for multiple of the estimated correlations support the hypothesis that both daily exposure levels to PM and VOC and duration of excessive exposure over the WHO’s recommended limits are associated with tau biomarkers (plasma p-tau217, CSF p-tau217, CSF p-tau181, and tau PET burden) and that VOC exposure is also associated with amyloid and neurodegeneration biomarkers (plasma/CSF Aβ42/40, amyloid PET amyloid burden, CSF NfL, and cortical thickness). To rigorously test these hypotheses, larger studies are needed. We hence performed a power analysis to determine the sample sizes needed to test these hypotheses for future studies. Figure 5 presents the sample sizes (n) needed for a future study with 80% statistical power to test a single correlation at 5% level, and multiple correlations of multiple air pollutant exposure measures with multiple AD biomarkers of AD at 5% level with rigorous Bonferroni’s adjustment. These power analyses were based on a two-sided standard normal test after the Fisher’s Z-transformation 37 . The direction of the correlation was assumed positive, but the results apply when the direction of the correlation is negative as well. 4. DISCUSSION Associations of air pollutant exposure with AD in general, and AD biomarkers in particular, remain poorly understood. In a recently updated meta-analysis 38 , the authors concluded that “strong conclusions remain elusive, although the weight of the evidence suggests an adverse association between PM 2.5 and cognitive decline”, and further noted “a continued need to confront methodological challenges in this line of research.” A major methodological challenge is that all existing research linking air pollutant exposure with AD biomarkers is based on regional, not person-specific, measurements from government agencies (EPA and EEA) outdoor ambient air quality monitoring. For example, only ~15 monitoring stations of PM are currently used in the entire State of Missouri, each providing a single measurement of PM levels to a large neighboring region at each time. Our pilot study indicated that the use of region-level measurements of outdoor ambient PM exposure in associational analyses with person-level measurements of AD biomarkers leads to significant bias in the estimated effect size, and reduces the statistical power. One explanation is that these data ignore the potentially large within-region variation of outdoor air quality and indoor air quality. More specifically, we found that a commercially available and wearable air quality sensor provides reliable and valid person-specific measurements of both outdoor and indoor air pollutant exposure, which further demonstrated that substantial between-individual variation exists in person-specific measurements of air pollutant exposure from participants within the same region at the same time. We also found that person-specific measures of air pollutant exposure lead to less biased estimates to the correlations between air pollutant exposure and AD biomarkers in comparison to region-level data of air pollution provided by the government agencies. Perhaps most importantly, our pilot study suggested that person-specific exposure to PM, and time exposed to excessive levels of PM over WHO’s recommended limits, correlated with tau biomarkers, and the correlations with amyloid biomarkers seemed to be relatively weak. These preliminary findings are not entirely consistent with the current and limited literature that mostly reported associations of PM 2.5 with CSF amyloid beta or amyloid PET biomarkers. Because these reports were entirely based on region-level PM exposure, given our finding that region-level exposure data may lead to substantial bias in association analyses with AD biomarkers, the inconsistency highlights the need to obtain person-specific air pollutant exposure in future large correlational studies between air pollution and AD biomarkers. Interestingly, we found that person-specific exposure to VOC is not only correlated with tau biomarkers, but also with amyloid biomarkers. Given that concentrations of VOC are up to ten times higher indoors than outdoors 39 , our pilot data suggest that it is important to measure both person-specific indoor and outdoor air quality, as they may influence AD biomarkers. We also found that the amount of time exposed to excessive levels of VOC may be correlated with MRI-based neurodegeneration biomarkers including structural outcomes, implying that air pollution may contribute to the neurodegeneration that is associated with AD. Finally, our pilot data seem to confirm that person-specific air pollutant exposure may depend on the characteristics of neighborhoods people live in and the associated SDOH. These results may imply that in future large studies to associate person-specific air pollutant exposure with AD biomarkers, SDOH such as littering in the neighborhoods and how people feel about their neighborhoods are important factors to consider in the design and analyses of these studies. Our pilot study focused on the associations of person-specific air pollutant exposure with AD biomarkers among individuals who were mostly cognitively normal or at very early symptomatic stages of AD. Because of converging scientific evidence that indicates neurodegenerative processes associated with AD may begin at middle age 40-41 and years or even decades prior to symptom onset when the disease is clinically at the early latent stage 42-44 , biomarkers from biofluid and imaging have guided recent clinical trials on AD by allowing trialists to confirm AD pathology in impaired and cognitively normal individuals (for treatment and prevention trials, respectively) and to conduct efficacy analyses on AD pathology. Hence, biomarkers of AD have played a central role in the recent success of disease-modifying therapies of AD that targeted amyloid pathology 45-46 . However, it remains unknown whether the treatment effects may be confounded with air pollutant exposure because these trials did not obtain person-specific measures of air pollutant exposure. Our findings, if confirmed by large and representative future longitudinal studies, may inform future design and analysis of natural history studies and clinical trials for prevention and treatment of AD to adequately account for possible contributions of air pollutant exposure to AD biomarkers and design these studies to appropriately control the effect of air pollution in comparative analyses. The main strengths of this pilot study include the person-specific measurements of air pollutant exposure including both indoor and outdoor exposures, and availability of AD biomarkers from all modalities, including plasma, CSF, amyloid PET, tau PET, and MRI. Main limitations of the pilot study include small sample size, lack of mechanism assessment between air pollution and AD biomarkers, and lack of longitudinal data. Future large and longitudinal studies are needed to obtain both person-specific air pollutant exposure and AD biomarkers, as well as potentially thousands of different exposure chemicals and metabolites in blood that may be linked with both air pollutant exposure and AD biomarkers. Declarations ACKNOWLEDGEMENTS NONE CONFLICTS Drs. Xiong, Schindler, Shriver, Benzinger, and Morris all have received research funding from the National Institute on Aging of the National Institutes of Health that was made to their institutions. Dr. Hall has received research funding from the National Institute for Occupational Safety and Health of the Centers for Disease Control that was made to his institution. Dr. Morris is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276; Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Xiong consults for Diadem and Intune Bio. There are no conflicts. Drs. Xiong and Benzinger and Hall served on Data Safety Monitoring Board or Advisory Boards for FDA and/or NIH-funded studies. There are no conflicts. Dr. Schindler has served on advisory boards or received speaker fees from Eisai, Eli Lilly, and Novo Nordisk. Dr. Benzinger has had consulting agreements with Biogen, Eisai, Merck, and Jansen. There are no conflicts. Dr. Benzinger received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Lilly, Peer View, and Medscape. There are no conflicts. Dr. Benzinger has had research grants from Siemens Healthineers and Hyperfine. Avid Radiopharmacueticals (a wholly owned subsidiary of Eli Lilly) , LMI and Lantheus have provided reagents and technology transfer agreements to Dr. Benzinger’s institution for the production of radiopharmaceuticals. 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PMID: 22488240; PMCID: PMC3586223 van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T (2023) Lecanemab in Early Alzheimer's Disease. N Engl J Med 388(1):9–21. 10.1056/NEJMoa2212948 Epub 2022 Nov 29. PMID: 36449413 Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, Wessels AM, Shcherbinin S, Wang H, Monkul Nery ES, Collins EC, Solomon P, Salloway S, Apostolova LG, Hansson O, Ritchie C, Brooks DA, Mintun M, Skovronsky DM (2023) TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 330(6):512–527. 10.1001/jama.2023.13239 PMID: 37459141; PMCID: PMC10352931 Tables Tables 1 and 2 are available in the Supplementary Files section Additional Declarations The authors declare no competing interests. Supplementary Files SupplementalTable19162024.jpg Supplemental Table 1: airpollutionTable19162024.jpg Table 1: airpollutionTable29162024.jpg Table 2: Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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phone\u003c/p\u003e","description":"","filename":"airpollutionFig19162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/ddaf5f62f270b4374732e041.jpg"},{"id":65203325,"identity":"bfbc520c-0ca6-4fe8-bbe1-94cd93597048","added_by":"auto","created_at":"2024-09-24 17:25:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":300356,"visible":true,"origin":"","legend":"\u003cp\u003eIntraclass correlation coefficient (ICC) of air pollutant exposure over the course of a day. The ICC (y-axis) was computed for each index (PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10\u003c/sub\u003e, and VOC) between every possible pair of adjacent time windows of 15 minutes each (starting and endpoint at midnight), and shown as a function of the starting time. A smoothed ICC curve for each index was obtained by the method of Locally Estimated Scatterplot Smoothing (LOESS).\u003c/p\u003e","description":"","filename":"airpollutionFig29162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/2169bcc896fa3bc5c530e900.jpg"},{"id":65203324,"identity":"da7319f1-f4b1-42c2-b2fc-6f8bc294f792","added_by":"auto","created_at":"2024-09-24 17:25:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":132784,"visible":true,"origin":"","legend":"\u003cp\u003eBetween- and within-individual variations of PM\u003csub\u003e2.5\u003c/sub\u003e levels from 8 participants of the same region and in the same 24 hours on 12/01/2023 (different colors represent different participants).\u003c/p\u003e","description":"","filename":"airpollutionFig39162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/028ecde8545bfeb4edf35fa8.jpg"},{"id":65203328,"identity":"0deca15a-3ce4-445e-9e3c-f7f74f7ca297","added_by":"auto","created_at":"2024-09-24 17:25:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":180610,"visible":true,"origin":"","legend":"\u003cp\u003eBias (left vertical axis, red color) and loss of statistical power (right vertical axis, green color) for the estimated correlation between an air pollutant exposure index and an AD biomarker when a proportion of participants (p) had only region-level data on air pollutant exposure (two true correlations were plotted: 0.15 in solid line and 0.45 in dashed line).\u003c/p\u003e","description":"","filename":"airpollutionFig49162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/f064c90a3352914a25ada2ee.jpg"},{"id":65202804,"identity":"a1b1cdef-59f5-49ba-be5f-04ea038884a1","added_by":"auto","created_at":"2024-09-24 17:17:28","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":136664,"visible":true,"origin":"","legend":"\u003cp\u003eSample sizes (n) needed with 80% power for a future study to test a single correlation or multiple correlations (with Bonferroni’s adjustment) between person-specific air pollutant exposure and AD biomarkers at 5% significance level.\u003c/p\u003e","description":"","filename":"airpollutionFig59162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/47c2df218ef01f6dd145a8b7.jpg"},{"id":65203538,"identity":"44b413f4-7842-4f76-82ba-91655a8df1bc","added_by":"auto","created_at":"2024-09-24 17:33:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1288956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/ec120e93-3c10-442e-a6a8-a2dffdcbddb3.pdf"},{"id":65202801,"identity":"554c4e90-41ec-49f6-b2cf-9d6c59fd3865","added_by":"auto","created_at":"2024-09-24 17:17:28","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":155401,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Table 1:\u0026nbsp;\u003c/p\u003e","description":"","filename":"SupplementalTable19162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/75fc6b04ea866c355bad254d.jpg"},{"id":65202799,"identity":"6393128d-ad57-4a78-b152-9a4d26f43ba5","added_by":"auto","created_at":"2024-09-24 17:17:28","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":127156,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1:\u003c/p\u003e","description":"","filename":"airpollutionTable19162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/5ba02316ad0e65b0e61ff8ab.jpg"},{"id":65203326,"identity":"26b13697-3a27-4716-a0dc-af4d480551a2","added_by":"auto","created_at":"2024-09-24 17:25:28","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":213884,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2:\u003c/p\u003e","description":"","filename":"airpollutionTable29162024.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5118913/v1/865384beaab242117e9e9fe1.jpg"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePerson-specific digitally measured air pollutant exposure and biomarkers of Alzheimer disease: findings from a pilot study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1.\tBACKGROUND","content":"\u003cp\u003eMany environmental factors are associated with Alzheimer disease (AD) and related dementia (ADRD)\u003csup\u003e1-3\u003c/sup\u003e. In 2019 the World Health Organization (WHO) estimated that ~99% of the world population was living in regions where the levels of air pollutants exceeded the WHO air quality guidelines. Fine particulate matter (PM) is\u0026nbsp;a mixture of solid particles and liquid droplets found in the air. Recent studies have found that higher exposure to the finest PM with diameters of 2.5 micrometers or smaller (called PM\u003csub\u003e2.5\u003c/sub\u003e) was associated with lower concentrations of\u0026nbsp;A\u0026beta;42\u003csup\u003e1\u003c/sup\u003e in cerebrospinal fluid (CSF), higher likelihood of a positive amyloid PET scan\u003csup\u003e2\u003c/sup\u003e, more amyloid plaques in autopsied brains\u003csup\u003e3\u003c/sup\u003e, and worse cognition with increased incidence of ADRD\u003csup\u003e4-5\u003c/sup\u003e. Higher levels of volatile organic compounds (VOC)\u0026nbsp;were also found in AD patients compared with normal controls\u003csup\u003e6-7\u003c/sup\u003e. However,\u0026nbsp;all existing research linking air pollutant exposure with AD biomarkers is based on regional, not person-specific, measurements of outdoor ambient air quality by government agencies (e.g., US Environmental Protection Agency [EPA] and European Environment Agency [EEA]). \u0026nbsp;Because region-level measures of air pollutant exposure\u0026nbsp;does not account for potentially large variability of outdoor air quality within regions or human factors due to mobility in daily life (e.g., time spent indoor vs. outdoor)\u0026nbsp;\u003csup\u003e8\u003c/sup\u003e, the use of region-level measurements of PM exposure in associational analyses with person-level measurements of AD biomarkers may lead to significant statistical bias in the estimated effect size and loss of statistical power.\u003c/p\u003e\n\u003cp\u003eThe objectives of this pilot study were to obtain person-specific data on air pollutant exposure to PM and VOC, and to generate hypotheses about their associations with person-specific AD\u0026nbsp;biomarkers. These biomarkers include\u0026nbsp;the\u0026nbsp;molecular imaging of amyloid and tau pathology with positron emission tomography (PET), plasma and\u0026nbsp;cerebrospinal fluid (CSF) analytes\u003csup\u003e10-11\u003c/sup\u003e, brain volumes as measured by magnetic resonance imaging (MRI), and cognitive outcomes.\u003c/p\u003e"},{"header":"2.\tMETHODS","content":"\u003cp\u003e2.1.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Participants\u003c/p\u003e\n\u003cp\u003eThis study included older community-dwelling individuals recruited from the greater St. Louis, Missouri, metropolitan area and enrolled in the longitudinal studies of memory and aging at the Washington University (WU) Knight Alzheimer Disease Research Center (ADRC). Details of recruitment have been described\u003csup\u003e13-14\u003c/sup\u003e. Participants were predominantly cognitively normal at the time of the cross-sectional study, but some had early symptomatic AD (mild cognitive impairment, very mild dementia, or mild dementia with a typical AD dementia syndrome). Individuals were excluded if they had illnesses that could prevent participation in neuroimaging, or adversely affect cognition (e.g., metastatic cancer). The inclusion criteria for the current study were 1) availability of data of cognitive measures and AD biomarkers for at least one of the following biomarker modalities: plasma or CSF biomarkers; amyloid PET; structural MRI; and 2) normal cognition or early symptomatic AD. \u0026nbsp;Potential participants meeting inclusion criteria were\u0026nbsp;referred by Knight ADRC Clinical Core to the study, and then contacted by the study coordinator for their willingness to participate. All participants provided written informed consent at recruitment. The\u0026nbsp;WU Human Research Protection Office approved procedures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.2.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Demographics and social determinants of health\u003c/p\u003e\n\u003cp\u003eAge, sex, years of education, and self-identified race were collected. \u0026nbsp; Social determinants of health (SDOH) were assessed by a comprehensive battery that was recently developed at the Knight ADRC, referred to as the Social and Structural Determinants Influencing Aging and Dementia battery (SS-DIAD)\u003csup\u003e15\u0026nbsp;\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.3.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Clinical and cognitive assessments\u003c/p\u003e\n\u003cp\u003eThe Knight ADRC\u0026rsquo;s clinical and cognitive assessment protocols are consistent with that of the National Alzheimer Coordinating Center (NACC) Uniform Data Set (UDS)\u003csup\u003e16\u003c/sup\u003e. The NACC UDS includes standard diagnostic criteria for dementia and its differential diagnoses\u003csup\u003e17\u003c/sup\u003e,\u0026nbsp;and uses the\u0026nbsp;global Clinical Dementia Rating\u0026reg; (CDR\u0026reg;)\u003csup\u003e18 \u0026nbsp;\u003c/sup\u003eto\u0026nbsp;operationalize the presence or absence of dementia, and when present, the severity of dementia.\u0026nbsp;The UDS cognitive battery includes measures of episodic memory, working memory, semantic knowledge, executive function and attention, and visuospatial ability. All scales were oriented so that a larger score indicates better cognition. \u0026nbsp;Z-scores were computed by subtracting the mean from the individual test scores and dividing the difference by the standard deviation (SD). A global cognitive composite score was constructed by averaging Z-scores across tests, as previously described\u003csup\u003e19\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.4.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003cem\u003eAPOE\u003c/em\u003e genotypes\u003c/p\u003e\n\u003cp\u003eDetails of the\u0026nbsp;\u003cem\u003eAPOE\u003c/em\u003e genotyping protocols have been described previously\u003csup\u003e20\u003c/sup\u003e.\u0026nbsp;We dichotomized \u003cem\u003eAPOE\u003c/em\u003e \u003cem\u003e\u0026epsilon;\u003c/em\u003e4 carrier status as positive or negative, indicating presence of one or two \u003cem\u003eAPOE\u003c/em\u003e \u003cem\u003e\u0026epsilon;\u003c/em\u003e4 alleles, or none. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.5.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Digital collection of person-specific air pollutant exposure\u003c/p\u003e\n\u003cp\u003eDigital measurements of person-specific air pollutant exposure were obtained by a commercially available and wearable air quality sensor, Atmotube Pro by Atmotube\u003csup\u003e21\u003c/sup\u003e.\u0026nbsp;The device is designed with a carabiner so that it may be worn easily, and can be paired with a smartphone for pinging GPS coordinates (\u003cstrong\u003eFigure 1\u003c/strong\u003e). Participants were asked to wear the device continuously for 7 days as they navigated their daily life. PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10\u003c/sub\u003e, and VOC were measured about once every 5 minutes. Data were uploaded to the Cloud storage and then downloaded into our local secure servers for analyses after participants mailed their device back.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeasurement properties of person-specific air pollutant\u0026nbsp;exposure by Atmotube Pro have previously been established. Field and laboratory evaluations done by the South Coast Air Quality Monitoring District (AQMD) and its Air Quality-Sensor Performance Evaluation Center (AQ-SPEC) program\u003csup\u003e22\u003c/sup\u003e, \u0026nbsp;an independent government agency, showed very strong correlations of PM\u003csub\u003e1\u003c/sub\u003e \u0026amp; PM\u003csub\u003e2.5 \u0026nbsp;\u003c/sub\u003efrom Atmotube Pro sensors with EPA-approved Federal Equivalent Method (FEM) GRIMM in the laboratory evaluations (r \u0026gt; 0.99), and strong correlations with the same reference instrument in the field evaluation (0.79 \u0026lt;r\u0026sup2;\u0026lt; 0.90; \u0026nbsp;see the South Coast AQMD website). Test-retest reliability was provided in Section (Test-retest reliability of person-specific air pollutant exposure by Atmotube Pro) below.\u003c/p\u003e\n\u003cp\u003e2.6.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;CSF and plasma sample collection and analysis\u003c/p\u003e\n\u003cp\u003eBlood was collected at the time of lumbar puncture (LP) or clinical assessment. CSF samples (20-30 mL) were \u0026nbsp;collected at 8 AM after overnight fasting by gravity drip, briefly centrifuged at\u0026nbsp;low speed, and aliquoted into polypropylene tubes prior to freezing at \u0026ndash;80\u0026deg;C. All plasma\u0026nbsp;samples (fasted and non-fasted) were analyzed\u0026nbsp;at\u0026nbsp;C\u003ca target=\"_blank\"\u003e\u003csub\u003e2\u003c/sub\u003e\u003c/a\u003eN Diagnostics\u0026nbsp;with the\u0026nbsp;PrecivityAD\u0026trade;\u0026nbsp;assay for A\u0026beta;42/40 and the PrecivityAD2\u0026trade; for p-tau217, which has previously been described\u003csup\u003e23-\u003c/sup\u003e\u003csup\u003e24\u003c/sup\u003e. An automated immunoassay (LUMIPULSE G1200, Fujirebio, Malverne, PA) was used to\u0026nbsp;measure CSF concentrations of A\u0026beta;40, A\u0026beta;42, total tau (t-tau), p-tau181, and NfL\u003csup\u003e25-26\u003c/sup\u003e.\u0026nbsp;Plasma\u0026nbsp;NfL and GFAP were measured with Quanterix assay kits at WU on a HD-X analyzer\u003csup\u003e27-28\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.7.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Brain imaging scan collection and processing\u003c/p\u003e\n\u003cp\u003eThe WU MRI protocol was implemented\u0026nbsp;on 3T scanners\u0026nbsp;for a total of approximately 60 minutes, and provided high gray-white matter contrast (1mm x 1mm x 1 mm) MPRAGE T1-weighted volume acquisitions\u003csup\u003e29\u003c/sup\u003e.\u0026nbsp;PET PiB or Florbetapir (AV45) imaging and tau\u0026nbsp;Flortaucipir (AV1451) imaging were conducted\u0026nbsp;as detailed previously\u0026nbsp;\u003csup\u003e29-30\u003c/sup\u003e. Structural MRI processing steps include motion correction, if applicable, averaging across scans, and atlas transformation. Regional volumes and cortical thickness were obtained via the FreeSurfer image analysis suite\u003csup\u003e31\u003c/sup\u003e. Determination of the regions-of-interest (ROIs) and pipelines were previously described\u003csup\u003e\u0026nbsp;32\u003c/sup\u003e. FreeSurfer quality control (QC) criteria include (1) dural inclusion, gray matter exclusion, sulcus inclusion, cerebellum inclusion; (2) cerebellum, subcortical and hippocampus segmentation exclusion; \u0026nbsp;(3) white matter exclusion, and (4) lateral ventricle segmentation. Analyses were performed on adjusted volumetric measures after regressing for the effect of scanner platforms and with adjustment for head size\u003csup\u003e32\u003c/sup\u003e. \u0026nbsp;Amyloid and tau deposition in the ROIs was determined using FreeSurfer, and a\u0026nbsp;standardized uptake value ratio (SUVR) \u0026nbsp;with correction for partial volume effects was calculated\u003csup\u003e32\u003c/sup\u003e.\u0026nbsp;The cerebellum was chosen as the reference region. The mean amyloid cortical SUVR was calculated from FreeSurfer regions within the prefrontal cortex, precuneus, and temporal cortex\u003csup\u003e29\u003c/sup\u003e. \u0026nbsp;A centiloid scale to harmonize PET amyloid data from PiB and AV45\u003csup\u003e33\u0026nbsp;\u003c/sup\u003ewas developed, following the same level-2 calibration procedure in the original Centiloid Working Group paper\u003csup\u003e34\u003c/sup\u003e.\u0026nbsp;Tau PET scans were collected and processed as previously described\u003csup\u003e12\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e2.8.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Statistical analyses\u003c/p\u003e\n\u003cp\u003eWe first estimated the test-retest reliability of person-specific measurements of PM and VOC exposure over 7-days (i.e., the intraclass correlation coefficient (ICC))\u003csup\u003e35\u003c/sup\u003e, using within-person consecutive measurements every 15 minutes.\u0026nbsp;We then demonstrated that person-specific digital measurements of air pollutant exposure can capture between-individual variation in the same region and also within-individual variation in the same day by showing that participants from the same region do not share the same levels of PM exposure at the same time point, and that significant within-individual variation also existed across the 24 hours. We then conducted a simulation study to assess the potential bias and loss of statistical power when region-level measures of air pollutant exposure were used in the correlational analyses with AD biomarkers, in comparison to the person-specific measures. Finally, we\u0026nbsp;analyzed 7-day air pollutant exposure data to PM and VOC by extracting main features from the time series, and then correlated these features with the available AD biomarkers. The first feature was the average daily exposure. The second feature was\u0026nbsp;the proportion of time in 7 days that person-specific PM exposure levels were over the limit as recommended by the WHO (15 \u0026micro;g/m\u003csup\u003e3\u003c/sup\u003e for PM\u003csub\u003e1\u003c/sub\u003e and PM\u003csub\u003e2.5\u003c/sub\u003e, 45 \u0026micro;g/m\u003csup\u003e3\u003c/sup\u003e for PM\u003csub\u003e10\u003c/sub\u003e, and 0.05 ppm for VOC). \u0026nbsp; The third feature was the first function principal component (FFPC) after performing a functional principal component analysis (FPCA)\u003csup\u003e\u0026nbsp;36\u003c/sup\u003e of 7-day air pollutant exposure for each index.\u003c/p\u003e\n\u003cp\u003eThe association analysis was conducted to correlate each of the features from the 7-day air pollutant exposure with all AD biomarkers and cognitive outcomes that were obtained prior to the digital assessments of air pollutant exposure. Because not all participants had data on all biomarker modalities, each pairwise correlation with biomarkers and cognitive measures was estimated using the participants for whom the bivariate data were available. These pairwise correlations were tested for statistical significance by a standard normal test after the Fisher\u0026rsquo;s Z-transformation\u003csup\u003e37\u003c/sup\u003e.\u0026nbsp;This test was chosen because Fisher\u0026rsquo;s Z-transformation can be approximated by a normal distribution regardless of the sample sizes, assuring the validity of our tests for a large number of pairwise correlations estimated from a wide range of sample sizes. Because of the preliminary nature of the pilot study with a primary goal to generate possible hypotheses for a future definite study, no rigorous multiplicity adjustment was performed. \u0026nbsp; Estimates or correlations were adjusted for the effect of the time interval between digital collection of air pollutant exposure and AD biomarkers and cognition, and additionally adjusted for the effects other covariates: age, race, cognitive status, \u003cem\u003eAPOE\u003c/em\u003e \u0026epsilon;4\u0026nbsp;status, years of education, sex, and medical comorbidities.\u003c/p\u003e\n\u003cp\u003eFinally, after generating a set of hypotheses about the correlations between person-specific air pollutant exposure and AD biomarkers, we performed a power analysis to decide the sample sizes needed for future studies to rigorously test these hypotheses.\u0026nbsp;\u003c/p\u003e"},{"header":"3.\tRESULTS","content":"\u003cp\u003eA total of 59 individuals from the WU Knight ADRC participated in the pilot study. The participants had an average age of\u0026nbsp;76.28 y (SD=5.28y), an average of 16.29 (2.00) years of education, and were mostly female (58%) and predominantly White (85%) and cognitively normal (88%). About 39% of the participants were\u0026nbsp;\u003cem\u003eAPOE\u003c/em\u003e Ɛ4 carriers.\u0026nbsp;\u0026nbsp;In addition to digital assessment of air pollutant exposure over 7 days, all 59 participants in our pilot study had NACC UDS\u003csup\u003e16\u003c/sup\u003e. A subset had data on CSF\u0026nbsp;A\u0026beta;42/40, CSF total tau, p-tau181 (n=20) and multiple other\u0026nbsp;CSF tau species (217,153,175, 205, 231, n=14) concentrations, plasma\u0026nbsp;A\u0026beta;42/40 (n=54) and p-tau217 (n=22), cortical thickness and hippocampal volume (n=41), amyloid PET (n=35), and tau PET (n=33). Data collection of AD biomarkers and cognition occurred mostly prior to the data collection of air pollutant exposure, with a median time interval of between 0.9 y (cognition) and 5.9 y (CSF). \u003cstrong\u003eTable 1\u003c/strong\u003e presents the basic demographics of the study participants. A total of 57 participants had data on CSF\u0026nbsp;A\u0026beta;42/40\u0026nbsp;and/or amyloid PET, and\u0026nbsp;28 (49%) were amyloid positive by either CSF or PET amyloid measures.\u003c/p\u003e\n\u003cp\u003e3.1.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Test-retest reliability of person-specific air pollutant exposure by Atmotube Pro\u003c/p\u003e\n\u003cp\u003eFrom the 59 participants \u0026nbsp;who underwent 7-day person-specific measurements of PM exposure, the within-persons consecutive measurements every 15 minutes were used to estimate the test-retest reliability of PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10\u003c/sub\u003e, and VOC. \u003cstrong\u003eFigure 2\u003c/strong\u003e presents the estimated intraclass correlation coefficient (ICC) as a function of time during a randomly selected day of 24 hours starting from midnight across participants, indicating very good test-retest reliability of the person-specific measurements of PMand VOC by the device. \u0026nbsp;Not surprisingly, ICCs were lower around the earlymorning and lunch times, reflecting changes in the daily routine when air pollutant exposure was subject to sudden changes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.2.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Person-specific digital measurements of air pollutant exposure captured between-individual variation in the same region and within-individual variation in the same day\u003c/p\u003e\n\u003cp\u003eAmong the 59 participants who underwent 7-day digital collection of their air pollutant exposure, eight from the same St. Louis region were measured on the same day (12/01/2023). \u003cstrong\u003eFigure 3\u003c/strong\u003e presents the time course of PM\u003csub\u003e2.5\u003c/sub\u003e levels from the 8 participants from midnight to midnight, demonstrating that participants from the same region do not share the same levels of PM exposure at the same time point (as EPA\u0026rsquo;s region-level data would imply), and that significant within-individual variation existed across the 24 hours.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.3.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Statistical bias and loss of power when region-level measurements of air pollutant exposure were used in the correlational analyses with AD biomarkers\u003c/p\u003e\n\u003cp\u003eTo demonstrate the importance of person-specific measurements of air pollutant exposure, we simulated 5000 independent data sets to assess the statistical bias and loss of statistical power when a region-level PM exposure was correlated with a person-level AD biomarker. Each data set was originally simulated at the person level for both the PM exposure and biomarker over 100 participants from a bivariate normal distribution with a true correlation of 0.15 or 0.45. We then created the region-level PM exposure for a randomly selected subset of 100p% (0\u0026lt;p\u0026lt;1) participants, using the mean of the simulated person-specific exposures in the subset. Finally, we estimated the correlation between the PM exposure and biomarker and tested its statistical significance. \u003cstrong\u003eFigure 4\u003c/strong\u003e shows the mean bias (defined as the mean of the estimates minus the true correlation) of 5000 estimated correlations (left vertical axis; red color) from the true correlations (0.15= solid line, 0.45=dashed line) and mean loss of statistical power of 5000 tests (right vertical axis; green color) from the true powers, as functions of p, the proportion of subjects with only region-level data of PM exposure, demonstrating increasing bias and loss of statistical power as p increases. Note that, when person-level data were used in PM exposure, i.e., p=0, no bias (=0, left vertical axis) and no loss of statistical power (=0, right vertical axis) were observed.\u003c/p\u003e\n\u003cp\u003e3.4.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Correlation of person-specific exposure to PM and VOC with AD biomarkers\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe estimated Spearman correlations of person-specific daily PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, and PM\u003csub\u003e10\u0026nbsp;\u003c/sub\u003eexposure (averaged over 7 days) with CSF p-tau181 and total tau showed a strong statistical trend and ranged from 0.35 to 0.59. PM\u003csub\u003e10\u003c/sub\u003e exposure was also correlated with CSF p-tau153 (r=0.82, p=0.044) and showed a trend with the tau PET burden (r=0.22) and plasma p-tau217 (r=0.17). There was also a trend towards statistical significance in the correlation of VOC exposure with plasma p-tau217 (r=0.51, p=0.052), p-tau181 (r=0.41, p=0.134), and CSF p-tau217 (r=0.69, p=0.089). The estimated correlation of person-specific daily VOC level was -0.37 (p=0.210) with CSF\u0026nbsp;A\u0026beta;42/40,\u0026nbsp;-0.34 (p=0.019) with plasma\u0026nbsp;A\u0026beta;42, -0.16 (p=0.278) with plasma\u0026nbsp;A\u0026beta;42/40, and 0.20 (p=0.3) with amyloid PET centiloid.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;The FFPC derived from a functional principal component analysis (FPCA)\u003csup\u003e36\u0026nbsp;\u003c/sup\u003eof 7-day air pollutant exposure for each index captured most of the variation across subjects (86.49%, 86.28%, 86.11%, and 74.80%\u0026nbsp;for PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10 \u0026nbsp;\u003c/sub\u003eand VOC, respectively), and may be interpreted as person-specific \u0026lsquo;total exposure\u0026rsquo;.\u0026nbsp;The correlation matrix (\u003cstrong\u003eTable 2\u003c/strong\u003e) showed positive correlations of the FFPC for both PM and VOC with almost all tau biomarkers, and some were statistically significant (r=0.63, 0.60, and 0.60 between PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10 \u0026nbsp;\u003c/sub\u003eand CSF total tau, p\u0026lt;5%). The FFPC for VOC was marginally correlated with amyloid biomarkers (r=-0.41 with CSF\u0026nbsp;A\u0026beta;42/40, 0.45 with CSF\u0026nbsp;A\u0026beta;40, and 0.25 with PET amyloid). No correlations of air pollutant exposure were found with cognitive composite.\u003c/p\u003e\n\u003cp\u003e3.5.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Correlations of person-specific time exposed to PM levels over WHO\u0026rsquo;s recommended limit correlated with AD biomarkers\u003c/p\u003e\n\u003cp\u003eUsing WHO\u0026rsquo;s recommended limits for daily PMand VOC exposure, we computed the proportion of time over 7 days that person-specific PM exposure levels were over the limit for each participant.\u0026nbsp;Times of excessive exposure to PM\u003csub\u003e1\u003c/sub\u003e,\u0026nbsp;PM\u003csub\u003e2.5\u003c/sub\u003e, and PM\u003csub\u003e10\u003c/sub\u003e were all significantly correlated with CSF total tau (r=0.85, 0.82, and 0.72, p=0.0002, 0.0005, and 0.006, respectively), and showed a statistical trend with CSF p-tau181 (r=0.36, 0.38, and 0.31, respectively). Time of excessive exposure to VOC was also marginally correlated with CSF\u0026nbsp;A\u0026beta;42\u0026nbsp;(r=-0.2),\u0026nbsp;plasma NfL (r=0.25) and cortical thickness (r=-0.18).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.6.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Correlation of person-specific exposure to PM and VOC with SDOH\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough not significant, we found a statistical trend indicating that people who reported living in very littered neighborhoods were exposed to higher levels of PM\u003csub\u003e10\u003c/sub\u003e (r=0.24, p=0.131), and those feeling a strong sense of belonging to their neighborhoods were exposed to less VOC (r=-0.34 with the FFPC, p=0.03).\u003c/p\u003e\n\u003cp\u003e3.7.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Sample sizes needed in a future study to power the test of the observed correlations\u003c/p\u003e\n\u003cp\u003eDue to small sample size in our pilot study, very few of these correlations reported above were statistically significant after adjusting for multiple comparisons. \u0026nbsp;However, multiple AD biomarkers had correlations with pollutants in the same direction (great biomarker abnormality was associated with higher levels of pollutants), suggesting a relationship between AD and pollution. More specifically, the statistical trends and relatively large magnitude for multiple of the estimated correlations support the hypothesis that both daily exposure levels to PM and VOC and duration of excessive exposure over the WHO\u0026rsquo;s recommended limits are associated with tau biomarkers\u0026nbsp;(plasma p-tau217, CSF p-tau217, CSF p-tau181, and tau PET burden)\u0026nbsp;and that VOC exposure is also associated with amyloid and neurodegeneration biomarkers (plasma/CSF\u0026nbsp;A\u0026beta;42/40, amyloid\u0026nbsp;PET amyloid burden, CSF NfL, and cortical thickness).\u0026nbsp;To rigorously test these hypotheses, larger studies are needed. We hence performed a power analysis to determine the sample sizes needed to test these hypotheses for future studies. \u003cstrong\u003eFigure 5\u003c/strong\u003e presents the sample sizes (n) needed for a future study with 80% statistical power to test a single correlation at 5% level, and multiple correlations of multiple air pollutant exposure measures with multiple AD biomarkers of AD at 5% level with rigorous Bonferroni\u0026rsquo;s adjustment. These power analyses were based on a two-sided standard normal test after the Fisher\u0026rsquo;s Z-transformation\u003cstrong\u003e\u003csup\u003e37\u003c/sup\u003e\u003c/strong\u003e. The direction of the correlation was assumed positive, but the results apply when the direction of the correlation is negative as well.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eAssociations of air pollutant exposure with AD in general, and AD biomarkers in particular, remain poorly understood. In a recently updated meta-analysis\u003csup\u003e38\u003c/sup\u003e,\u0026nbsp;the authors concluded that \u0026ldquo;strong conclusions remain elusive, although the weight of the evidence suggests an adverse association between PM\u003csub\u003e2.5 \u0026nbsp;\u003c/sub\u003eand cognitive decline\u0026rdquo;, and further noted \u0026ldquo;a continued need to confront methodological challenges in this line of research.\u0026rdquo; A major methodological challenge is that\u0026nbsp;all existing research linking air pollutant exposure with AD biomarkers is based on regional, not person-specific, measurements from government agencies (EPA and EEA) outdoor ambient air quality monitoring. For example, only ~15 monitoring stations of PM are currently used in the entire State of Missouri, each providing a single measurement of PM levels to a large neighboring region at each time. Our pilot study indicated that the use of region-level measurements of outdoor ambient PM exposure in associational analyses with person-level measurements of AD biomarkers leads to significant bias in the estimated effect size, and reduces the statistical power. One explanation is that these data ignore the potentially large within-region variation of outdoor air quality and indoor air quality. More specifically, we found that a commercially available and wearable air quality sensor provides reliable and valid person-specific measurements of both outdoor and indoor air pollutant exposure, which further demonstrated that substantial between-individual variation exists in person-specific measurements of air pollutant exposure from participants within the same region at the same time. We also found that person-specific measures of air pollutant exposure lead to less biased estimates to the correlations between air pollutant exposure and AD biomarkers in comparison to region-level data of air pollution provided by the government agencies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePerhaps most importantly, our pilot study suggested that person-specific exposure to PM, and time exposed to excessive levels of PM over WHO\u0026rsquo;s recommended limits, correlated with tau biomarkers, and the correlations with amyloid biomarkers seemed to be relatively weak. These preliminary findings are not entirely consistent with the current and limited literature that mostly reported associations of PM\u003csub\u003e2.5\u003c/sub\u003e with CSF amyloid beta or amyloid PET biomarkers. Because these reports were entirely based on region-level PM exposure, given our finding that region-level exposure data may lead to substantial bias in association analyses with AD biomarkers, the inconsistency highlights the need to obtain person-specific air pollutant exposure in future large correlational studies between air pollution and AD biomarkers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, we found that person-specific exposure to VOC is not only correlated with tau biomarkers, but also with amyloid biomarkers. Given that concentrations of VOC are up to ten times higher indoors than outdoors\u003csup\u003e39\u003c/sup\u003e, our pilot data suggest that it is important to measure both person-specific indoor and outdoor air quality, as they may influence AD biomarkers. We also found that the amount of time exposed to excessive levels of VOC may be correlated with MRI-based neurodegeneration biomarkers including structural outcomes, implying that air pollution may contribute to the neurodegeneration that is associated with AD. Finally, our pilot data seem to confirm that person-specific air pollutant exposure may depend on the characteristics of neighborhoods people live in and the associated SDOH. These results may imply that in future large studies to associate person-specific air pollutant exposure with AD biomarkers, SDOH such as littering in the neighborhoods and how people feel about their neighborhoods are important factors to consider in the design and analyses of these studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur pilot study focused on the associations of person-specific air pollutant exposure with AD biomarkers among individuals who were mostly cognitively normal or at very early symptomatic stages of AD. Because of converging scientific evidence that indicates neurodegenerative processes associated with AD may begin at middle age\u0026nbsp;\u003csup\u003e40-41\u003c/sup\u003e and years or even decades prior to symptom onset when the disease is clinically at the early latent stage\u003csup\u003e42-44\u003c/sup\u003e, biomarkers from biofluid and imaging have guided recent clinical trials on AD by allowing trialists to confirm AD pathology in impaired and cognitively normal individuals (for treatment and prevention trials, respectively) and to conduct efficacy analyses on AD pathology. Hence, biomarkers of AD have played a central role in the recent success of disease-modifying therapies of AD that targeted amyloid pathology\u003csup\u003e45-46\u003c/sup\u003e. However, it remains unknown whether the treatment effects may be confounded with air pollutant exposure because these trials did not obtain person-specific measures of air pollutant exposure. Our findings, if confirmed by large and representative future longitudinal studies, may inform future design and analysis of natural history studies and clinical trials for prevention and treatment of AD to adequately account for possible contributions of air pollutant exposure to AD biomarkers and design these studies to appropriately control the effect of air pollution in comparative analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The main strengths of this pilot study include the person-specific measurements of air pollutant exposure including both indoor and outdoor exposures, and availability of AD biomarkers from all modalities, including plasma, CSF, amyloid PET, tau PET, and MRI. Main limitations of the pilot study include small sample size, lack of mechanism assessment between air pollution and AD biomarkers, and lack of longitudinal data. Future large and longitudinal studies are needed to obtain both person-specific air pollutant exposure and AD biomarkers, as well as potentially thousands of different exposure chemicals and metabolites in blood that may be linked with both air pollutant exposure and AD biomarkers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNONE\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrs. Xiong, Schindler, Shriver, Benzinger, and Morris all have\u0026nbsp;received research funding from the National Institute on Aging of the National Institutes of Health that was made to their institutions.\u003c/p\u003e\n\u003cp\u003eDr. Hall has received research funding from the National Institute for Occupational Safety and Health of the Centers for Disease Control that was made to his institution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr. Morris is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company.\u003c/p\u003e\n\u003cp\u003eDr. Xiong consults for Diadem and Intune Bio. There are no conflicts.\u003c/p\u003e\n\u003cp\u003eDrs. Xiong and Benzinger and Hall served on Data Safety Monitoring Board or Advisory Boards for FDA and/or NIH-funded studies.\u0026nbsp;There are no conflicts.\u003c/p\u003e\n\u003cp\u003eDr. Schindler has served on advisory boards or received speaker fees from Eisai, Eli Lilly, and Novo Nordisk.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr. Benzinger has had consulting agreements with Biogen, Eisai, Merck, and Jansen. There are no conflicts.\u003c/p\u003e\n\u003cp\u003eDr. Benzinger received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Lilly, Peer View, and Medscape.\u0026nbsp;There are no conflicts.\u003c/p\u003e\n\u003cp\u003eDr. Benzinger has had research grants from Siemens Healthineers and Hyperfine.\u003c/p\u003e\n\u003cp\u003eAvid Radiopharmacueticals (a wholly owned subsidiary of Eli Lilly) , LMI and Lantheus have provided reagents and technology transfer agreements to Dr. Benzinger\u0026rsquo;s institution for the production of radiopharmaceuticals.\u003c/p\u003e\n\u003cp\u003eDr. Lu, Dr. Bui, Dr. Moulder, Mr. Popp, Ms. Agboola, and Ms. Gremminger have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING SOURCES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNONE\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComplete written informed consent was obtained from the participants who have data as part of this publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCasey E, Li Z, Liang D, Ebelt S, Levey AI, Lah JJ, Wingo TS, H\u0026uuml;ls A (2024) Association between Fine Particulate Matter Exposure and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease among a Cognitively Healthy Population-Based Cohort. 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Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 330(6):512\u0026ndash;527. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2023.13239\u003c/span\u003e\u003cspan address=\"10.1001/jama.2023.13239\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 37459141; PMCID: PMC10352931\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Washington University in St. Louis School of Medicine","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer disease, CSF biomarkers, Imaging biomarkers, particulate matter, volatile organic compound","lastPublishedDoi":"10.21203/rs.3.rs-5118913/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5118913/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBACKGROUND: \u003c/strong\u003ePerson-specific measures of particulate matter (PM) and volatile organic compounds (VOC) may better associate with Alzheimer disease (AD) biomarkers, including plasma and cerebrospinal fluid (CSF) analytes and amyloid and tau positron emission tomography (PET) signal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETHODS: \u003c/strong\u003eFifty nine older participants underwent 7-day digital collection of exposure to PM and VOC by Atmotube Pro, a validated wearable air quality sensor. Person-specific levels of PM and\u0026nbsp; VOC were correlated with biomarkers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS: \u003c/strong\u003eThe first functional principal components (FFPC) of PM and VOC captured 75% to 86% of the total variation, and were correlated with tau biomarkers (r=0.63, 0.60, and 0.60 between PM\u003csub\u003e1\u003c/sub\u003e, PM\u003csub\u003e2.5\u003c/sub\u003e, PM\u003csub\u003e10\u0026nbsp; \u003c/sub\u003eand CSF total tau, respectively; p\u0026lt;5%). The FFPC of VOC was marginally correlated with amyloid biomarkers (r=-0.41 with CSF Aβ42/40, r=0.45 with CSF Aβ40, and r=0.25 with PET amyloid centiloid).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCUSSION: \u003c/strong\u003ePerson-level air pollutant exposure is associated with AD biomarkers, but larger and longitudinal studies are needed.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Person-specific digitally measured air pollutant exposure and biomarkers of Alzheimer disease: findings from a pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-24 17:17:23","doi":"10.21203/rs.3.rs-5118913/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"75f683d1-8402-4ef7-8720-26e1f6a42fdf","owner":[],"postedDate":"September 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-24T17:17:23+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-24 17:17:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5118913","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5118913","identity":"rs-5118913","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}