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This is because of the spatial discordance between amyloid-\u03b2, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during ageing. There is evidence that in some cases amyloid-\u03b2-independent tau spreads beyond the medial temporal lobe where it may interact with neocortical amyloid-\u03b2. This suggests that there may be multiple distinct spatiotemporal subtypes of Alzheimer's-related protein aggregation, with potentially different demographic and genetic risk profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post-mortem neuropathology and in vivo PET-based measures from two large observational studies: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP).<\/jats:p>\n                  <jats:p>We consistently identified \u2018amyloid-first\u2019 and \u2018tau-first\u2019 subtypes using cross-sectional information from both studies. In the amyloid-first subtype, extensive neocortical amyloid-\u03b2 precedes the spread of tau beyond the medial temporal lobe, while in the tau-first subtype, mild tau accumulates in medial temporal and neocortical areas prior to interacting with amyloid-\u03b2. As expected, we found a higher prevalence of the amyloid-first subtype among apolipoprotein E (APOE) \u03b54 allele carriers while the tau-first subtype was more common among APOE \u03b54 non-carriers. Within tau-first APOE \u03b54 carriers, we found an increased rate of amyloid-\u03b2 accumulation (via longitudinal amyloid PET), suggesting that this rare group may belong within the Alzheimer's disease continuum. We also found that tau-first APOE \u03b54 carriers had several fewer years of education than other groups, suggesting a role for modifiable risk factors in facilitating amyloid-\u03b2-independent tau. Tau-first APOE \u03b54 non-carriers, in contrast, recapitulated many of the features of primary age-related tauopathy. The rate of longitudinal amyloid-\u03b2 and tau accumulation (both measured via PET) within this group did not differ from normal ageing, supporting the distinction of primary age-related tauopathy from Alzheimer's disease. We also found reduced longitudinal subtype consistency within tau-first APOE \u03b54 non-carriers, suggesting additional heterogeneity within this group.<\/jats:p>\n                  <jats:p>Our findings support the idea that amyloid-\u03b2 and tau may begin as independent processes in spatially disconnected regions, with widespread neocortical tau resulting from the local interaction of amyloid-\u03b2 and tau. The site of this interaction may be subtype-dependent: medial temporal lobe in amyloid-first, neocortex in tau-first. These insights into the dynamics of amyloid-\u03b2 and tau may inform research and clinical trials that target these pathologies.<\/jats:p>","DOI":"10.1093\/brain\/awad232","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T14:41:03Z","timestamp":1689086463000},"page":"4935-4948","source":"Crossref","is-referenced-by-count":65,"title":["A data-driven study of Alzheimer's disease related amyloid and tau pathology progression"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2342-0780","authenticated-orcid":false,"given":"Leon M","family":"Aksman","sequence":"first","affiliation":[{"name":"Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California , Los Angeles, CA 90033 , USA"},{"name":"Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-3909","authenticated-orcid":false,"given":"Neil P","family":"Oxtoby","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia A","family":"Scelsi","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4885-6241","authenticated-orcid":false,"given":"Peter A","family":"Wijeratne","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7772-781X","authenticated-orcid":false,"given":"Alexandra L","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London , London SE5 8AF , UK"},{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora Lopes","family":"Alves","sequence":"additional","affiliation":[{"name":"Brain Research Center , Amsterdam 1081 GN , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6263-1762","authenticated-orcid":false,"given":"Lyduine E","family":"Collij","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam 1007MB , The Netherlands"},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-9940","authenticated-orcid":false,"given":"Jacob W","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pennsylvania , Philadelphia, PA 19104 , USA"},{"name":"Lifespan Informatics and Neuroimaging Center, University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London , London WC1V 6LJ , UK"},{"name":"Brain Research Center , Amsterdam 1081 GN , The Netherlands"},{"name":"Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam 1007MB , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C","family":"Alexander","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2393","authenticated-orcid":false,"given":"Andre","family":"Altmann","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the 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