{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:46:14Z","timestamp":1789069574888,"version":"build-2803163510"},"reference-count":112,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MHLW Research on rare and intractable diseases Program","award":["JPMH23FC1008"],"award-info":[{"award-number":["JPMH23FC1008"]}]},{"name":"JSPS-KAKENHI","award":["JP23K06935"],"award-info":[{"award-number":["JP23K06935"]}]},{"name":"JSPS-KAKENHI","award":["JP25K22597"],"award-info":[{"award-number":["JP25K22597"]}]},{"name":"JSPS-KAKENHI","award":["JP25K10781"],"award-info":[{"award-number":["JP25K10781"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-\u03b2 (A\u03b2)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, A\u03b2 pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with A\u03b2 depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the \u2018amyloid cascade\u2019 and \u2018tauopathy\u2019 hypotheses. From the \u2018amyloid cascade\u2019 viewpoint, A\u03b2 deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal A\u03b2 pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the \u2018tauopathy\u2019 perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by A\u03b2 pathology and also differ from the system degeneration seen in other tauopathies.<\/jats:p>","DOI":"10.3390\/ijms262412088","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:00:26Z","timestamp":1765882826000},"page":"12088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Determinant of Tau Spreading in Alzheimer\u2019s Disease: Dependent on Senile Plaque, Neural Circuits, or Spatial Proximity?"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6493-8976","authenticated-orcid":false,"given":"Yuichi","family":"Riku","sequence":"first","affiliation":[{"name":"Institute for Medical Science of Aging, Aichi Medical University, Nagakute 480-1195, Aichi, Japan"},{"name":"Department of Neurology, Nagoya University, Nagoya 466-8550, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Brion","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research (UCDR), Faculty of Medicine, ULB Neuroscience Institute (UNI), Universit\u00e9 Libre de Bruxelles, 1050 Bruxelles, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-175X","authenticated-orcid":false,"given":"Kunie","family":"Ando","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research (UCDR), Faculty of Medicine, ULB Neuroscience Institute (UNI), Universit\u00e9 Libre de Bruxelles, 1050 Bruxelles, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Uchihara","sequence":"additional","affiliation":[{"name":"Okinawa Chubu Hospital, Uruma 904-2293, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Institute for Medical Science of Aging, Aichi Medical University, Nagakute 480-1195, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD 2021 Nervous System Disorders Collaborators (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol., 23, 344\u2013381. Correction in Lancet Neurol. 2024, 23, e9. Correction in Lancet Neurol. 2024, 23, e11.","DOI":"10.1016\/S1474-4422(24)00231-X"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70436","DOI":"10.1002\/alz.70436","article-title":"The burden of cognitive impairment","volume":"21","author":"Gracner","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/ca.980080612","article-title":"An English translation of Alzheimer\u2019s 1907 paper, \u201cUber eine eigenartige Erkankung der Hirnrinde\u201d","volume":"8","author":"Alzheimer","year":"1995","journal-title":"Clin. Anat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000211873","article-title":"Miliare Nekrosen mit drusingen Wucherungen der Neurofibrillen, eine regelm\u00e4ssige Ver\u00e4nderung der Hirnrinde bei seniler Demenz","volume":"22","author":"Fischer","year":"1907","journal-title":"Monattsschrift Psychiatr. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1093\/jnen\/nlac030","article-title":"A History of Senile Plaques: From Alzheimer to Amyloid Imaging","volume":"81","author":"Beach","year":"2022","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_6","first-page":"445","article-title":"Sur les l\u00e9sions et la pathog\u00e9nie de l\u2019\u00e9pilepsie dite essentielle","volume":"12","author":"Blocq","year":"1892","journal-title":"Sem. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1001\/jamaneurol.2015.0202","article-title":"Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease","volume":"72","author":"Tarawneh","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1038\/s43587-024-00731-y","article-title":"Diagnosis of Alzheimer\u2019s disease using plasma biomarkers adjusted to clinical probability","volume":"4","author":"Therriault","year":"2024","journal-title":"Nat. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1038\/s41380-025-03081-2","article-title":"Advance and Prospect of Positron Emission Tomography in Alzheimer\u2019s disease research","volume":"30","author":"Wang","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1097\/WCO.0000000000001098","article-title":"Neuropathology and neuroanatomy of TDP-43 amyotrophic lateral sclerosis","volume":"35","author":"Braak","year":"2022","journal-title":"Curr. Opin. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Arnold, F.J., Putka, A.F., Raychaudhuri, U., Hsu, S., Bedlack, R.S., Bennett, C.L., and La Spada, A.R. (2024). Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115587"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: A practical approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"271\u2013278; discussion 278\u2013284","DOI":"10.1016\/0197-4580(95)00021-6","article-title":"Staging of Alzheimer\u2019s disease-related neurofibrillary changes","volume":"16","author":"Braak","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of A45Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3233\/JAD-2006-9S321","article-title":"Immunological demonstration of tau protein in neurofibrillary tangles of Alzheimer\u2019s disease","volume":"9","author":"Brion","year":"2006","journal-title":"J. Alzheimers Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16391","DOI":"10.1038\/s41598-024-65949-7","article-title":"A novel monoclonal antibody generated by immunization with granular tau oligomers binds to tau aggregates at 423-430 amino acid sequence","volume":"14","author":"Soeda","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s40478-014-0161-3","article-title":"Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy","volume":"2","author":"Tatsumi","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nrn.2015.1","article-title":"Tau in physiology and pathology","volume":"17","author":"Wang","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1046\/j.1365-2990.2003.00463.x","article-title":"Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies","volume":"29","author":"Lashley","year":"2003","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00401-013-1097-6","article-title":"Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology","volume":"125","author":"Hara","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0165-0173(00)00019-9","article-title":"Tau protein isoforms, phosphorylation and role in neurodegenerative disorders","volume":"33","author":"Delacourte","year":"2000","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/jnen\/59.8.723","article-title":"Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects","volume":"59","author":"Yamaguchi","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1093\/jnen\/60.11.1051","article-title":"Cotton wool plaques in non-familial late-onset Alzheimer disease","volume":"60","author":"Le","year":"2001","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00401-020-02198-8","article-title":"The coarse-grained plaque: A divergent A\u03b2 plaque-type in early-onset Alzheimer\u2019s disease","volume":"140","author":"Boon","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0306-4522(01)00169-5","article-title":"The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer\u2019s disease","volume":"105","author":"Dickson","year":"2001","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1097\/NEN.0b013e31825018f7","article-title":"Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature","volume":"71","author":"Nelson","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1172\/JCI23269","article-title":"Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice","volume":"115","author":"Brendza","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1126\/science.1131864","article-title":"Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host","volume":"313","author":"Coomaraswamy","year":"2006","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1007\/s12035-023-03736-7","article-title":"Neuritic Plaques\u2014Gateways to Understanding Alzheimer\u2019s Disease","volume":"61","author":"Tsering","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration","volume":"173","author":"Deczkowska","year":"2018","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10634","DOI":"10.1038\/s41467-024-54779-w","article-title":"Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer\u2019s Disease","volume":"15","author":"Albertini","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"338ra66","DOI":"10.1126\/scitranslmed.aaf2362","article-title":"Tau and A\u03b2 imaging, CSF measures, and cognition in Alzheimer\u2019s disease","volume":"8","author":"Brier","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S1474-4422(11)70156-9","article-title":"Neuropathologically defined subtypes of Alzheimer\u2019s disease with distinct clinical characteristics: A retrospective study","volume":"10","author":"Murray","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/s43587-025-00835-z","article-title":"Plasma p-tau217 and tau-PET predict future cognitive decline among cognitively unimpaired individuals: Implications for clinical trials","volume":"5","author":"Ossenkoppele","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1126\/science.1141736","article-title":"Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer\u2019s disease mouse model","volume":"316","author":"Roberson","year":"2007","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1016\/j.ajpath.2012.08.012","article-title":"Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP\/PS1 mice","volume":"181","author":"Leroy","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S1474-4422(12)70307-1","article-title":"A presenilin 1 mutation in the first case of Alzheimer\u2019s disease","volume":"12","author":"Winter","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1042\/bj2750099","article-title":"Tau in Alzheimer\u2019s disease and Down\u2019s syndrome is insoluble and abnormally phosphorylated","volume":"275","author":"Hanger","year":"1991","journal-title":"Biochem. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.2353\/ajpath.2010.100346","article-title":"A-beta accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model","volume":"177","author":"Hurtado","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1750-3639.2007.00052.x","article-title":"Hereditary frontotemporal dementia caused by Tau gene mutations","volume":"17","author":"Spillantini","year":"2007","journal-title":"Brain Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature15369","article-title":"Evidence for human transmission of amyloid-\u03b2 pathology and cerebral amyloid angiopathy","volume":"525","author":"Jaunmuktane","year":"2015","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00401-018-1828-9","article-title":"Fatal A\u03b2 cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years","volume":"135","author":"Cabrejo","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00401-017-1703-0","article-title":"Amyloid-\u03b2 accumulation in the CNS in human growth hormone recipients in the UK","volume":"134","author":"Ritchie","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00401-017-1791-x","article-title":"Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology","volume":"135","author":"Duyckaerts","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/s41591-023-02729-2","article-title":"Iatrogenic Alzheimer\u2019s disease in recipients of cadaveric pituitary-derived growth hormone","volume":"30","author":"Banerjee","year":"2024","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1523\/JNEUROSCI.20-10-03606.2000","article-title":"Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice","volume":"20","author":"Kane","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1073\/pnas.1017033108","article-title":"Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration","volume":"108","author":"Jin","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1062097","article-title":"Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils","volume":"293","author":"Chen","year":"2001","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1126\/science.1058189","article-title":"Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP","volume":"293","author":"Lewis","year":"2001","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.nbd.2013.09.010","article-title":"Increased misfolding and truncation of tau in APP\/PS1\/tau transgenic mice compared to mutant tau mice","volume":"62","author":"Goufak","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nm.4443","article-title":"Amyloid-\u03b2 plaques enhance Alzheimer\u2019s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation","volume":"24","author":"He","year":"2018","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00401-018-1953-5","article-title":"Amyloid-\u03b2 pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo","volume":"137","author":"Vergara","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00401-015-1390-7","article-title":"PART is part of Alzheimer disease","volume":"129","author":"Duyckaerts","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1046\/j.1440-1789.2003.00522.x","article-title":"Senile dementia of the neurofibrillary tangle type (tangle-only dementia): Neuropathological criteria and clinical guidelines for diagnosis","volume":"23","author":"Yamada","year":"2003","journal-title":"Neuropathology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1212\/WNL.0000000000003636","article-title":"Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations","volume":"88","author":"Spina","year":"2017","journal-title":"Neurology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/s41594-025-01498-5","article-title":"Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W","volume":"32","author":"Qi","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00401-022-02467-8","article-title":"Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer\u2019s dementia","volume":"144","author":"Sanchez","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/jnen\/nly010","article-title":"Detection of Alzheimer Disease (AD)-Specific Tau Pathology in AD and NonAD Tauopathies by Immunohistochemistry with Novel Conformation-Selective Tau Antibodies","volume":"77","author":"Gibbons","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00401-018-1855-6","article-title":"Tau seeding activity begins in the transentorhinal\/entorhinal regions and anticipates phospho-tau pathology in Alzheimer\u2019s disease and PART","volume":"136","author":"Kaufman","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00401-021-02294-3","article-title":"Cryo-EM structures of tau filaments from Alzheimer\u2019s disease with PET ligand APN-1607","volume":"141","author":"Shi","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1038\/s41467-025-56469-7","article-title":"Early Alzheimer\u2019s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy","volume":"16","author":"Browne","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1097\/00005072-199311000-00009","article-title":"Re-evaluation of the structural organization of neuritic plaques in Alzheimer\u2019s disease","volume":"52","author":"Masliah","year":"1993","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_67","first-page":"352","article-title":"Comparative epitope analysis of neuronal cytoskeletal proteins in Alzheimer\u2019s disease senile plaque neurites and neuropil threads","volume":"64","author":"Schmidt","year":"1991","journal-title":"Lab. Investig."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00401-019-02108-7","article-title":"Human subiculo-fornico-mamillary system in Alzheimer\u2019s disease: Tau seeding by the pillar of the fornix","volume":"139","author":"Thierry","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00401-014-1322-y","article-title":"Inside Alzheimer brain with CLARITY: Senile plaques, neurofibrillary tangles and axons in 3-D","volume":"128","author":"Ando","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1007\/BF00687379","article-title":"Senile plaque neurites fail to demonstrate anti-paired helical filament and anti-microtubule-associated protein-tau immunoreactive proteins in the absence of neurofibrillary tangles in the neocortex","volume":"77","author":"Probst","year":"1989","journal-title":"Acta Neuropathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/BF03160121","article-title":"Continuity of neuropil threads with tangle-bearing and tangle-free neurons in Alzheimer disease cortex. A confocal laser scanning microscopy study","volume":"18","author":"Schmidt","year":"1993","journal-title":"Mol. Chem. Neuropathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s00401-025-02862-x","article-title":"Sequence and trajectory of early Alzheimer\u2019s disease-related tau inclusions in the hippocampal formation of cases without amyloid-\u03b2 deposits","volume":"149","author":"Braak","year":"2025","journal-title":"Acta Neuropathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/BF00308817","article-title":"Senile dementia of the Alzheimer type: Is there a correlation between entorhinal cortex and dentate gyrus lesions?","volume":"82","author":"Senut","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1159\/000017104","article-title":"Progression of Alzheimer-related neuritic plaque pathology in the entorhinal region, perirhinal cortex and hippocampal formation","volume":"10","author":"Hanke","year":"1999","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00401-015-1392-5","article-title":"Nucleus basalis of Meynert revisited: Anatomy, history and differential involvement in Alzheimer\u2019s and Parkinson\u2019s disease","volume":"129","author":"Liu","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1093\/brain\/awae325","article-title":"Amyloid-\u03b2 predominant Alzheimer\u2019s disease neuropathologic change","volume":"148","author":"Kovacs","year":"2025","journal-title":"Brain"},{"key":"ref_77","unstructured":"Duyckaerts, C., and Christen, Y. (1997). Connections, Cognition and Alzheimer diseaseons, Cognition and Alzheimer disease. Research and Perspective in Alzheimer\u2019s Disease, Springer."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-009-0532-1","article-title":"Classification and basic pathology of Alzheimer disease","volume":"118","author":"Duyckaerts","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1126\/science.6474172","article-title":"Alzheimer\u2019s disease: Cell-specific pathology isolates the hippocampal formation","volume":"225","author":"Hyman","year":"1984","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1093\/brain\/aws239","article-title":"In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer\u2019s disease","volume":"135","author":"Hornberger","year":"2012","journal-title":"Brain"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1046\/j.1365-2990.1998.00108.x","article-title":"Amyotrophic lateral sclerosis: Current issues in classification, pathogenesis and molecular pathology","volume":"24","author":"Ince","year":"1998","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1001\/jamaneurol.2013.5489","article-title":"Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"71","author":"Riku","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"9878","DOI":"10.1523\/JNEUROSCI.1138-17.2019","article-title":"The Salience Network: A Neural System for Perceiving and Responding to Homeostatic Demands","volume":"39","author":"Seeley","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1126\/science.1194732","article-title":"The neural basis of intuitive best next-move generation in board game experts","volume":"331","author":"Wan","year":"2011","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/jnen\/nlw053","article-title":"Marked Involvement of the Striatal Efferent System in TAR DNA-Binding Protein 43\u2009kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis","volume":"75","author":"Riku","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1093\/jnen\/nlx055","article-title":"Pathologic Involvement of Glutamatergic Striatal Inputs from the Cortices in TAR DNA-Binding Protein 43\u2009kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis","volume":"76","author":"Riku","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/neup.12823","article-title":"Simple and clear differentiation of spinocerebellar degenerations: Overview of macroscopic and low-power view findings","volume":"42","author":"Iwabuchi","year":"2022","journal-title":"Neuropathology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s40478-016-0388-2","article-title":"Hippocampal phospho-tau\/MAPT neuropathology in the fornix in Alzheimer disease: An immunohistochemical autopsy study","volume":"4","author":"Plowey","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00401-008-0447-2","article-title":"Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: Distinction from Alzheimer disease","volume":"117","author":"Takeda","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_90","unstructured":"Terry, R.D., Katzman, R., Bick, K.L., and Sisodia, S.S. (1999). The cellular basis of cortical disconnection in Alzheimer disease and related dementing conditions. Alzheimer Disease, Lipincott Williams & Wilkins. [2nd ed.]."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s004010050645","article-title":"Dissociation of Alzheimer type pathology in a disconnected piece of cortex","volume":"93","author":"Duyckaerts","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s40478-017-0488-7","article-title":"What is the evidence that tau pathology spreads through prion-like propagation?","volume":"5","author":"Mudher","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1038\/s41374-021-00644-z","article-title":"Exosomal tau with seeding activity is released from Alzheimer\u2019s disease synapses, and seeding potential is associated with amyloid beta","volume":"101","author":"Miyoshi","year":"2021","journal-title":"Lab. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8490","DOI":"10.1038\/ncomms9490","article-title":"Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer\u2019s disease brain","volume":"6","author":"Takeda","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00401-014-1373-0","article-title":"Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer\u2019s disease or corticobasal degeneration brains","volume":"129","author":"Boluda","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1901","article-title":"Transmission and spreading of tauopathy in transgenic mouse brain","volume":"11","author":"Clavaguera","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1016\/j.ajpath.2016.06.008","article-title":"High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo","volume":"186","author":"Audouard","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1038\/s41593-025-01992-5","article-title":"Evidence for trans-synaptic propagation of oligomeric tau in human progressive supranuclear palsy","volume":"28","author":"McGeachan","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"24479","DOI":"10.1074\/jbc.M603971200","article-title":"RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion","volume":"281","author":"Kar","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.gene.2009.11.006","article-title":"Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations","volume":"451","author":"Wang","year":"2010","journal-title":"Gene"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Storbeck, M., Hupperich, K., Gaspar, J.A., Meganathan, K., Mart\u00ednez Carrera, L., Wirth, R., Sachinidis, A., and Wirth, B. (2014). Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089020"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1093\/brain\/awac091","article-title":"Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration","volume":"145","author":"Riku","year":"2022","journal-title":"Brain"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.celrep.2017.01.013","article-title":"Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes","volume":"18","author":"Ishigaki","year":"2017","journal-title":"Cell Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.bbadis.2004.06.015","article-title":"Transcriptional and conformational changes of the tau molecule in Alzheimer\u2019s disease","volume":"1739","author":"Hyman","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1111\/j.1471-4159.2005.03641.x","article-title":"Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer\u2019s disease","volume":"96","author":"Ginsberg","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Li, L.L., Wang, R.Z., Wang, Z., Hu, H., Xu, W., Zhu, L., Sun, Y., Chen, K.L., Chen, S.F., and He, X.Y. (2025). Safety and short-term outcomes of lecanemab for Alzheimer\u2019s disease in China: A multicentre study. Brain, epub ahead print.","DOI":"10.1093\/brain\/awaf427"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s13195-022-01124-2","article-title":"Lecanemab in patients with early Alzheimer\u2019s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study","volume":"14","author":"McDade","year":"2022","journal-title":"Alzheimers Res. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e70750","DOI":"10.1002\/alz.70750","article-title":"Lecanemab treatment for Alzheimer\u2019s Disease of varying severities and associated plasma biomarkers monitoring: A multi-center real-world study in China","volume":"21","author":"Chen","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"25424823251395615","DOI":"10.1177\/25424823251395615","article-title":"Combined 64-channel EEG and PET evaluation of lecanemab efficacy: Two case reports","volume":"9","author":"Wang","year":"2025","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"100163","DOI":"10.1016\/j.tjpad.2025.100163","article-title":"Challenges and opportunities for novel combination therapies in Alzheimer\u2019s disease: A report from the EU\/US CTAD Task Force","volume":"12","author":"Angioni","year":"2025","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e70734","DOI":"10.1002\/alz.70734","article-title":"Celebrating neuropathology\u2019s contributions to Alzheimer\u2019s Disease Research Centers","volume":"21","author":"Fischer","year":"2025","journal-title":"Alzheimers Dement."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12088\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:01:40Z","timestamp":1765882900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":112,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262412088"],"URL":"https:\/\/doi.org\/10.3390\/ijms262412088","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]}}}