{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T14:04:27Z","timestamp":1784988267919,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,22]]},"group-title":"Toxicology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["U01 AG088407, R01 AG072396, P30 AG072931"],"award-info":[{"award-number":["U01 AG088407, R01 AG072396, P30 AG072931"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"crossref","award":["P30 ES017885, R01 ES028802"],"award-info":[{"award-number":["P30 ES017885, R01 ES028802"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Lead (Pb) is associated with Alzheimer\u2019s disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>\n                    Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p\n                    <jats:sub>adj<\/jats:sub>\n                    &lt;0.05).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Consistent Pb response was observed at 25 genes (\n                    <jats:italic>INPP5F<\/jats:italic>\n                    ,\n                    <jats:italic>KIF20B<\/jats:italic>\n                    ,\n                    <jats:italic>KIFC1<\/jats:italic>\n                    ) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (\u22122.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes (\n                    <jats:italic>EHD3<\/jats:italic>\n                    ,\n                    <jats:italic>LAP3<\/jats:italic>\n                    ,\n                    <jats:italic>NRXN3<\/jats:italic>\n                    ,\n                    <jats:italic>PPP1R16B<\/jats:italic>\n                    ,\n                    <jats:italic>RPL29<\/jats:italic>\n                    ,\n                    <jats:italic>THRA)<\/jats:italic>\n                    and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.<\/jats:p>\n                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