{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:11:56Z","timestamp":1790327516389,"version":"4.1.0"},"reference-count":84,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82003361"],"award-info":[{"award-number":["82003361"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The piriform cortex (PIR) is a key region of the olfactory system and is increasingly implicated in Alzheimer's disease (AD). However, the cellular heterogeneity of principal neurons (PN) in this region and their selective vulnerability in AD remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we integrated single\u2010cell multi\u2010omics datasets to systematically characterize PIR PN heterogeneity. We identified four transcriptionally and epigenetically distinct PN subtypes with different spatial distributions across the anterior and posterior PIR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In AD mouse models, the abundance of the Reln\u2010positive superficial\u2010layer (Reln+ SL) subtype was spatially associated with amyloid\u2010\u03b2 pathology, and its reduced proportion was confirmed by multiplex immunofluorescence. Cross\u2010region comparison revealed that Reln+ SL neurons shared a\n                      <jats:italic>Gpc5<\/jats:italic>\n                      \u2010high\/\n                      <jats:italic>Sort1<\/jats:italic>\n                      \u2010low molecular signature with vulnerable layer II excitatory neurons in the entorhinal cortex (EC). In human AD, this vulnerability\u2010associated signature showed progressive enrichment in EC layer II neurons across Braak stages I\u2013III. Furthermore, A\n                      <jats:italic>Sort1<\/jats:italic>\n                      \u2010containing co\u2010expression module captured regional differences between lateral and medial EC layer II populations and was enriched for proteostasis\u2010related pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings reveal shared molecular features associated with selective vulnerability across PIR and EC layer II neurons and identify a proteostasis\u2010related program linked to regional differences in neuronal vulnerability during AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Single\u2010cell multi\u2010omics reveals molecular heterogeneity among piriform cortex principal neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Reln+ superficial\u2010layer neurons show selective vulnerability in AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Cross\u2010region comparison identifies a shared\n                            <jats:italic>Gpc5<\/jats:italic>\n                            \u2010high\/\n                            <jats:italic>Sort1<\/jats:italic>\n                            \u2010low signature in vulnerable layer II neurons of EC and PIR.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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