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However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer\u2019s disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages.<\/jats:p>\n                  <jats:p>The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer\u2019s Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer\u2019s Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer\u2019s disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination.<\/jats:p>\n                  <jats:p>A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer\u2019s disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer\u2019s Disease Neuroimaging Initiative cohort.<\/jats:p>\n                  <jats:p>This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer\u2019s disease into four biological stages with distinct characteristics.<\/jats:p>","DOI":"10.1093\/brain\/awaf346","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T11:52:50Z","timestamp":1758196370000},"page":"1023-1034","source":"Crossref","is-referenced-by-count":14,"title":["Staging Alzheimer\u2019s disease through amyloid and tau PET"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4217-5517","authenticated-orcid":false,"given":"Derek R","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J","family":"Wiste","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1466-8357","authenticated-orcid":false,"given":"Christopher G","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6544-066X","authenticated-orcid":false,"given":"David S","family":"Knopman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-0589","authenticated-orcid":false,"given":"Prashanthi","family":"Vemuri","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8001-2081","authenticated-orcid":false,"given":"Kejal","family":"Kantarci","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-8187","authenticated-orcid":false,"given":"Bradley F","family":"Boeve","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2770-0691","authenticated-orcid":false,"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8128-4476","authenticated-orcid":false,"given":"Petrice M","family":"Cogswell","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C","family":"Senjem","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]},{"name":"Department of Information Technology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry M","family":"Therneau","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Griswold","sequence":"additional","affiliation":[{"name":"Department of Data Science, University of Mississippi Medical Center , Jackson, MS 39216 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Rochester, MN 55905 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