{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:19:56Z","timestamp":1790864396588,"version":"4.1.0"},"reference-count":67,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"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":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>\n                      Multiple\n                      <jats:italic>TREM2<\/jats:italic>\n                      variants are associated with an increased risk of Alzheimer's disease (AD).\n                      <jats:italic>TREM2<\/jats:italic>\n                      H157Y is the only variant located at the proteolytic cleavage site that enhances TREM2 protein shedding. While this variant is associated with increased AD risk predominantly in the Chinese population, its impact on AD pathology is largely unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We conducted an in\u2010depth study integrating clinical cases, neuroimaging data, and blood proteomic data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TREM2<\/jats:italic>\n                      H157Y variant carriers with AD exhibit more severe AD pathology, more severe neurodegeneration, and more rapid clinical progression. Cognitively normal individuals carrying the variant show changes in blood proteins that are associated with neurodegeneration and inflammation. Moreover, the\n                      <jats:italic>TREM2<\/jats:italic>\n                      H157Y variant is associated with altered immune and vascular processes irrespective of disease state.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      These findings highlight the clinical implications of the\n                      <jats:italic>TREM2<\/jats:italic>\n                      H157Y variant and the use of blood proteomic data to investigate the effects of genetic variants on disease\u2010related endophenotypes.\n                    <\/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>\n                            The\n                            <jats:italic>TREM2<\/jats:italic>\n                            H157Y variant is associated with more rapid clinical progression of Alzheimer's disease only in the presence of the apolipoprotein E (\n                            <jats:italic>APOE)<\/jats:italic>\n                            \u03b54 allele.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The\n                            <jats:italic>TREM2<\/jats:italic>\n                            H157Y variant is associated with neurodegeneration, irrespective of disease state.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The\n                            <jats:italic>TREM2<\/jats:italic>\n                            H157Y variant is associated with altered immune and vascular processes, irrespective of disease state.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Cognitively normal\n                            <jats:italic>TREM2<\/jats:italic>\n                            H157Y carriers show altered disease\u2010associated blood proteins related to peripheral immune response.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Blood proteomic data can be used to study the impacts of disease\u2010associated genetic variants on disease outcomes and biological processes involved in pathogenesis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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