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While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA\u2010binding protein 43 (TDP\u201043) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP\u201043 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP\u201043 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP\u201043 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP\u201043 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic\u2010predominant age\u2010related TDP\u201043 encephalopathy and pinpointing of the optimal timing for testing anti\u2010tau and anti\u2010TDP\u201043 treatments in trials.<\/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>Both tau and TAR DNA\u2010binding protein 43 (TDP\u201043) pathology contribute to medial temporal lobe atrophy.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>There is a positive association between tau and TDP\u201043 and potentially a synergism.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>It is unclear if tau and TDP\u201043 have an additive or synergistic effect on atrophy.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The relative timing of the tau and TDP\u201043 effects on atrophy remains unclear.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Clarifying the interplay between tau and TDP\u201043 will help improve magnetic resonance imaging biomarkers.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14582","type":"journal-article","created":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T09:48:41Z","timestamp":1740217721000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Role of tau versus TDP\u201043 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Laura E. 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National Laboratory Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-8100","authenticated-orcid":false,"given":"Renaud","family":"La Joie","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences University of California San Francisco San Francisco California 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