{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T06:00:05Z","timestamp":1785477605440,"version":"3.56.0"},"reference-count":60,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>We examined the impact of mid\u2010life metabolites on late\u2010life Alzheimer's disease (AD) plasma biomarkers and whether these metabolites mediate air pollution effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      In the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort, we applied high\u2010dimensional regression and mediation models, adjusting for observed and latent confounders, with replication in the Atherosclerosis Risk in Communities (ARIC) study. Exposures included mid\u2010life fine particulate matter (PM\n                      <jats:sub>2.5<\/jats:sub>\n                      ), black carbon, metals, and metabolites. Outcomes were: late\u2010life plasma p\u2010tau(181, 217, and 231) and amyloid beta 42\/40 (Simoa assays).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      In the Heart SCORE study, seven lipid\u2010 and amnio acid\u2010pathway metabolites measured in mid\u2010life were significantly inversely associated with late\u2010life p\u2010tau181 levels (false discovery rate \u2264 15%) and showed a nominal inverse association with p\u2010tau217 and 231 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). 2\u2010aminobutyrate was associated with mid\u2010life PM\n                      <jats:sub>2.5<\/jats:sub>\n                      concentration (\u00b5g\/m\n                      <jats:sup>3<\/jats:sup>\n                      ;\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u00a0=\u00a0\u22120.047;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a04.0\u00a0\u00d7\u00a010\u22124) and mediated the effect of PM\n                      <jats:sub>2.5<\/jats:sub>\n                      on p\u2010tau181 (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0057). Independent replication in the ARIC study confirmed the inverse association.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Mid\u2010life metabolite profiles, particularly 2\u2010aminobutyrate, may predict and mediate air pollution\u2013related AD risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Seven mid\u2010life metabolites were inversely linked to late\u2010life plasma phosphorylated tau (p\u2010tau)181.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            2\u2010aminobutyrate was tied to fine particulate matter (PM\n                            <jats:sub>2.5<\/jats:sub>\n                            ), black carbon, and heavy metal exposure in two independent cohorts.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>2\u2010aminobutyrate may link pollution to Alzheimer's disease (AD) via oxidative stress pathways.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This effect is specific to p\u2010tau181, a marker of early AD changes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This is the evidence of a metabolic mediator between air pollution and AD risk.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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