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We investigate mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration on tau\u2010induced domain\u2010specific cognitive impairment in amyloid\u2010beta (A\u03b2) positive cognitively normal and impaired adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We assessed magnetic resonance imaging\u2013derived MTL and neocortical volume\/thickness and\n                      <jats:sup>18<\/jats:sup>\n                      F\u2010Flortaucipir positron emission tomography in 319 A\u03b2\u2010positive individuals. Cognitive functions across six domains were isolated by adjusting for other cognitive measures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>MTL tau correlated with memory subdomains, neocortical tau with executive function, and both with semantic fluency. Specific structural measures partially mediated these tau\u2013cognition associations: Brodmann area 35 mediated tau\u2013immediate and tau\u2013delayed recall, posterior hippocampus tau\u2013recognition, and inferior temporal cortex tau\u2013semantic fluency associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings provide a nuanced understanding of region\u2010specific macrostructural atrophy as one pathway of tau\u2010induced cognitive changes, aligning with known tau spread patterns. Additionally, isolating cognitive functions is a promising approach for future research.<\/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>Medial temporal lobe tau was related to memory domains; neocortical tau to executive function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Both tau positron emission tomography measures were associated with semantic fluency.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Specific regional atrophy partially mediated tau\u2010induced cognitive changes.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Other mechanistic links between tau and cognitive subdomains require investigation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Isolated cognitive domains should be explored as future avenues of research.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70511","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T09:18:37Z","timestamp":1753435117000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tau, atrophy, and domain\u2010specific cognitive impairment in typical Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-3388","authenticated-orcid":false,"given":"Anika","family":"Wuestefeld","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6 Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7184-7028","authenticated-orcid":false,"given":"Long","family":"Xie","sequence":"additional","affiliation":[{"name":"Penn Image Computing and Science Laboratory (PICSL) University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Radiology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"McGrew","sequence":"additional","affiliation":[{"name":"Penn Image Computing and Science Laboratory (PICSL) University of Pennsylvania  Philadelphia Pennsylvania 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