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Despite extensive investigations into its origins, the etiology of ALS\/PDC remains unclear. ALS\/PDC is, at the neuropathology level, characterized by tau-dominant multiple proteinopathy in brain and spinal cord. It was recently reported that Guam ALS\/PDC brain extracts exhibit tau seeding activity in fluorescence resonance energy transfer (FRET)-based biosensor cells. To build upon those findings and explore the nature of tau seeds in ALS\/PDC in more detail, we used an alanine mutational scanning (Ala scan) approach to determine the seeding profile of tau in nervous tissues of Guam ALS\/PDC cases. First, we confirmed the detection of tau seeding activity in ALS\/PDC brain samples in tau biosensor cells. Notably, we could also detect potent tau seeding activity in spinal cord. Subsequent Ala scan assays demonstrated that ALS\/PDC tau displays an aggregate incorporation pattern that resembles that of chronic traumatic encephalopathy (CTE)-type tau. This result is consistent with recent electron cryo-microscopy studies of tau, which revealed that ALS\/PDC tau filaments are predominantly of the CTE-type. The structural characteristics and seeding behavior of ALS\/PDC tau, as well as the regional distribution of tau pathology at post-mortem, suggest that ALS\/PDC is a CTE-like tauopathy.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Neurodegenerative tauopathies are characterized by proteinaceous deposits containing microtubule-associated tau in nervous tissue. Emerging evidence suggests that disease-associated tau proteins adopt abnormal, self-propagating conformations characteristic of prions. Here, we employed alanine mutational scanning (Ala scan) to determine the nature of prion-like tau seeds in ALS\/PDC, a mysterious disorder that occurred formerly in high incidence in certain regions in the western Pacific. We show that the Ala scan incorporation profile of ALS\/PDC tau is similar to that of abnormal tau proteins in chronic traumatic encephalopathy (CTE). The findings lend support to the idea that ALS\/PDC can be classified structurally as a CTE-like tauopathy. This work may have important implications for our understanding of ALS\/PDC as well as common neurological disorders beyond the Pacific.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.22.696002","type":"posted-content","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T19:15:17Z","timestamp":1766690117000},"source":"Crossref","is-referenced-by-count":1,"title":["Guam amyotrophic lateral sclerosis\/parkinsonism-dementia complex (ALS\/PDC) features CTE-like tau seeds in brain and spinal cord"],"prefix":"10.64898","author":[{"given":"Nil","family":"Saez-Calveras","sequence":"first","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert M.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Morgan","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Hill","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prarthna","family":"Chabria","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler","family":"Taylor","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyomitsu","family":"Oyanagi","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiyoshi","family":"Kakita","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz A.","family":"Joachimiak","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Vaquer-Alicea","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8085-7770","authenticated-orcid":false,"given":"Marc I.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Neurodegenerative Diseases, Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062814000995000_2025.12.22.696002v2.1","unstructured":"H. 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