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The medial temporal lobe (MTL), an early site of Alzheimer\u2019s disease pathology, is also a common target of co-pathologies, such as limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), often following an anterior-to-posterior atrophy gradient. Given the susceptibility of MTL to co-pathologies, here we explored T-N mismatch specifically within MTL using plasma ptau217 and MTL morphometry for identifying vulnerabilities and resilience in cognitively impaired or unimpaired patients with Alzheimer\u2019s disease.<\/jats:p>\n                  <jats:p>We parcellated the MTL into 100 spatially contiguous segments and calculated their T-N mismatch using plasma ptau217 as a measure for T and thickness as a marker of N.\u00a0Based on these mismatch profiles, we clustered 447 amyloid-positive individuals from the Alzheimer\u2019s Disease Neuroimaging Initiative cohort into data-driven T-N phenotypes. We characterized the T-N phenotypes by examining their cross-sectional and longitudinal atrophy both within the MTL and across the whole brain, in addition to cognitive trajectories. This framework was replicated in an independent cohort and, finally, translated to a real-world clinical sample of 50 patients undergoing anti-amyloid therapy.<\/jats:p>\n                  <jats:p>Clustering identified three T-N phenotypes with different MTL T-N mismatch profiles, atrophy patterns and cognitive outcomes, despite comparable Alzheimer\u2019s disease severity. The \u2018canonical\u2019 group, characterized by low T-N residuals (N \u223c T), showed Alzheimer\u2019s disease-like neurodegeneration patterns. The \u2018vulnerable\u2019 group, characterized by disproportionately greater neurodegeneration than tau (N &amp;gt; T), showed atrophy primarily in the anterior MTL that extended into temporal-limbic regions, in both cross-sectional and longitudinal analyses. This group also exhibited neurodegeneration that preceded estimated tau onset and experienced faster cognitive decline across multiple domains, aligning with the typical characteristics of mixed LATE-NC with Alzheimer\u2019s disease. In contrast, the \u2018resilient\u2019 group (N &amp;lt; T) showed minimal atrophy and preserved cognitive function. These phenotypes were reproducible in an independent research cohort. Importantly, in a feasibility study applying the model developed from the Alzheimer\u2019s Disease Neuroimaging Initiative to a clinical cohort of patients receiving lecanemab, we identified vulnerable individuals with LATE-like atrophy patterns. This highlights its potential utility for identifying individuals with co-pathology in clinical settings.<\/jats:p>\n                  <jats:p>Our findings demonstrate that T-N mismatch within MTL using MRI and plasma biomarkers can reveal Alzheimer\u2019s disease groups with varying vulnerability\/resilience, with the vulnerable group displaying structural and cognitive outcomes suggestive of LATE-NC. This approach offers a cost-effective strategy for clinical trial stratification and precision medicine for Alzheimer\u2019s disease therapeutics.<\/jats:p>","DOI":"10.1093\/brain\/awag105","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:51:19Z","timestamp":1776430279000},"source":"Crossref","is-referenced-by-count":3,"title":["Medial temporal lobe tau\u2013neurodegeneration mismatch from structural imaging and plasma biomarkers"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0958-132X","authenticated-orcid":false,"given":"Xueying","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi S","family":"Mundada","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2057-3976","authenticated-orcid":false,"given":"Christopher A","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niyousha","family":"Sadeghpour","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"McGrew","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Wuestefeld","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Lund University , Lund SE-221 00 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0312-5530","authenticated-orcid":false,"given":"Michael Tran","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Gee","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya M","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice S","family":"Chen-Plotkin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Mechanic-Hamilton","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura \u00a0E \u00a0M","family":"Wisse","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Lund, Lund University , Lund SE-221 00 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-4016","authenticated-orcid":false,"given":"Paul A","family":"Yushkevich","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhitsu\u00a0R","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Wolk","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"2026101319212493000_awag105-B1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement"},{"key":"2026101319212493000_awag105-B2","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s association 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