{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:47:27Z","timestamp":1790750847765,"version":"4.1.0"},"reference-count":81,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2022,5,31]]},"abstract":"<jats:p>Background: Neurofibrillary tangle (NFT) accumulation in the entorhinal cortex (EC) precedes the transformation from cognitive controls to mild cognitive impairment and Alzheimer\u2019s disease (AD). While tauopathy has been described in the EC before, the order and degree to which the individual subfields within the EC are engulfed by NFTs in aging and the preclinical AD stage is unknown. Objective: We aimed to investigate substructures within the EC to map the populations of cortical neurons most vulnerable to tau pathology in aging and the preclinical AD stage. Methods: We characterized phosphorylated tau (CP13) in 10 cases at eight well-defined anterior-posterior levels and assessed NFT density within the eight entorhinal subfields (described by Insausti and colleagues) at the preclinical stages of AD. We validated with immunohistochemistry and labeled the NFT density ratings on ex vivo MRIs. We measured subfield cortical thickness and reconstructed the labels as three-dimensional isosurfaces, resulting in anatomically comprehensive, histopathologically validated tau \u201cheat maps.\u201d Results: We found the lateral EC subfields ELc, ECL, and ECs (lateral portion) to have the highest tau density in semi-quantitative scores and quantitative measurements. We observed significant stepwise higher tau from anterior to posterior levels (p\u200a&lt;\u200a0.001). We report an age-dependent anatomically-specific vulnerability, with all cases showing posterior tau pathology, yet older individuals displaying an additional anterior tau burden. Finally, cortical thickness of each subfield negatively correlated with respective tau scores (p\u200a&lt;\u200a0.05). Conclusion: Our findings indicate that posterior-lateral subfields within the EC are the most vulnerable to early NFTs and atrophy in aging and preclinical AD.<\/jats:p>","DOI":"10.3233\/jad-215567","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T13:58:27Z","timestamp":1650981507000},"page":"1379-1399","source":"Crossref","is-referenced-by-count":34,"title":["Entorhinal Subfield Vulnerability to Neurofibrillary Tangles in Aging and the Preclinical Stage of Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"87","author":[{"given":"Josu\u00e9","family":"Llamas-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Oltmer","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas N.","family":"Greve","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Slepneva","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruopeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Champion","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Lang-Orsini","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Fischl","sequence":"additional","affiliation":[{"name":"Department of Radiology, Athinoula A. 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