{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T22:53:50Z","timestamp":1789080830388,"version":"build-2803163510"},"reference-count":68,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"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":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Transactive response DNA binding protein 43 kDa (TDP\u201043) proteinopathy has been linked to cognitive decline and often co\u2010occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP\u201043 proteinopathy and HS, we performed genome\u2010wide association studies (GWASs) of HS and TDP\u201043 inclusions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS:\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a09509; TDP\u201043:\n                      <jats:italic>N\u00a0<\/jats:italic>\n                      =\u00a04669). Statistical analyses included association analysis with HS and TDP\u201043 inclusions and meta\u2010analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B\n                      <jats:italic>(<\/jats:italic>\n                      <jats:italic>TMEM106B)<\/jats:italic>\n                      region.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Two regions achieved genome\u2010wide significance with TDP\u201043: apolipoprotein E (\n                      <jats:italic>APOE)<\/jats:italic>\n                      and\n                      <jats:italic>TMEM106B<\/jats:italic>\n                      . Three loci reached genome\u2010wide significance with HS:\n                      <jats:italic>APOE<\/jats:italic>\n                      ,\n                      <jats:italic>TMEM106B<\/jats:italic>\n                      , and granulin precursor (\n                      <jats:italic>GRN)<\/jats:italic>\n                      . Fine mapping of\n                      <jats:italic>TMEM106B<\/jats:italic>\n                      identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP\u201043 proteinopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>We identified associations with TDP\u201043 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic\u2010predominant age\u2010related TDP\u201043 encephalopathy.<\/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>HS and TDP\u201043 contribute to dementia and often co\u2010occur.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The etiology and relationship of HS and TDP\u201043 remains unclear.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            HS and TDP\u201043 share genetic risk factors in the genes\n                            <jats:italic>APOE<\/jats:italic>\n                            and\n                            <jats:italic>TMEM106B<\/jats:italic>\n                            .\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Genes have direct effects on HS, with additional effects mediated through TDP\u201043.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70760","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:04:17Z","timestamp":1762769057000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genome\u2010wide association studies of TDP\u201043 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B"],"prefix":"10.1002","volume":"21","author":[{"given":"Dana","family":"Godrich","sequence":"first","affiliation":[{"name":"Dr. John T. 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MacDonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. Hussman Institute for Human Genomics Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"Naj","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology, and Informatics Penn Neurodegeneration Genomics Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Hamilton","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics Miller School of Medicine University of Miami  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan\u2010Ping","family":"Lee","sequence":"additional","affiliation":[{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Logan","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory &amp; Alzheimer's Center Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Mayeux","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Larson","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K.","family":"Crane","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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Ilyas","family":"Kamboh","sequence":"additional","affiliation":[{"name":"University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer's Disease Center Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Molina\u2010Porcel","sequence":"additional","affiliation":[{"name":"Neurology Service, Hospital Cl\u00ednic, Fundaci\u00f3 Recerca Cl\u00ednic Barcelona (FRCB). Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) University of Barcelona  Sarri\u00e0\u2010Sant Gervasi Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Schellenberg","sequence":"additional","affiliation":[{"name":"Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Pericak\u2010Vance","sequence":"additional","affiliation":[{"name":"Dr. John T. MacDonald Foundation Department of Human Genetics Miller School of Medicine University of Miami  Miami Florida USA"},{"name":"John P. 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