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                 <jats:p>Amyloid-\u03b2 (A\u03b2) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of A\u03b2, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related A\u03b2-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures.<\/jats:p>\n                  <jats:p>We included 545 cognitively unimpaired adults (40\u201392 years) from the BioFINDER-2 study (in vivo) and 639 (64\u2013108 years) from the Rush Alzheimer\u2019s Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global\/regional A\u03b2 in vivo. Immunohistochemistry was used to estimate A\u03b2 load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer\u2019s disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning.<\/jats:p>\n                  <jats:p>In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for A\u03b2. This was also observed in individuals with low A\u03b2 load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of A\u03b2. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer\u2019s disease pathology, i.e. early tau and\/or A\u03b2 pathology (subiculum\/Brodmann area 35\/precuneus\/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including A\u03b2-PET as covariate. Results were validated in the ex vivo cohort showing age-related and A\u03b2-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for A\u03b2 density.<\/jats:p>\n                  <jats:p>Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer\u2019s disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low A\u03b2 pathology.<\/jats:p>","DOI":"10.1093\/brain\/awad135","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T04:59:17Z","timestamp":1682053157000},"page":"3192-3205","source":"Crossref","is-referenced-by-count":54,"title":["Age-related and amyloid-beta-independent tau deposition and its downstream effects"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-3388","authenticated-orcid":false,"given":"Anika","family":"Wuestefeld","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Pichet Binette","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-1883","authenticated-orcid":false,"given":"David","family":"Berron","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"},{"name":"German Center for Neurodegenerative Diseases (DZNE) , 39120 Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-8788","authenticated-orcid":false,"given":"Nicola","family":"Spotorno","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8649-9874","authenticated-orcid":false,"given":"Danielle","family":"van Westen","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Clinical Sciences, Lund University , SE-222 42 Lund , Sweden"},{"name":"Image and Function, Sk\u00e5ne University Hospital , SE-205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Stomrud","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , SE-205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"},{"name":"Department of Neurology, Sk\u00e5ne University Hospital , SE-205 02 Malm\u00f6 , Sweden"},{"name":"Wallenberg Center for Molecular Medicine, Lund University , 221 84 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olof","family":"Strandberg","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-0112","authenticated-orcid":false,"given":"Ruben","family":"Smith","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"},{"name":"Department of Neurology, Sk\u00e5ne University Hospital , SE-205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-1930","authenticated-orcid":false,"given":"Sebastian","family":"Palmqvist","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences Malm\u00f6, Lund University , SE-222 42 Lund , Sweden"},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , SE-205 02 Malm\u00f6 , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Glenn","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine , Baltimore, MD 21287 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Moes","sequence":"additional","affiliation":[{"name":"Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. 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