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(p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer\u2019s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer\u2019s disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer\u2019s disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer\u2019s disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) (n\u2009=\u20091067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-\u03b2 PET scan at baseline. A subset of participants (n\u2009=\u2009864) also had measures of amyloid-\u03b21\u201342 and p-tau181 levels in CSF, and another subset (n\u2009=\u2009298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-\u03b2 pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer\u2019s disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-\u03b2 markers reached abnormal levels, with greater rates of change correlating with increased amyloid-\u03b2 pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-\u03b2 pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-\u03b2 were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer\u2019s disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels \u223c6.5 and 5.7 years after CSF and PET measures of amyloid-\u03b2, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-\u03b2 pathology and with prospective Alzheimer\u2019s disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awaa399","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T16:39:31Z","timestamp":1603730371000},"page":"325-339","source":"Crossref","is-referenced-by-count":212,"title":["Time course of phosphorylated-tau181 in blood across the Alzheimer\u2019s disease spectrum"],"prefix":"10.1093","volume":"144","author":[{"given":"Alexis","family":"Moscoso","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel J","family":"Grothe","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden"},{"name":"Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University 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Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6191-0954","authenticated-orcid":false,"given":"Anniina","family":"Snellman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden"},{"name":"Turku PET Centre, University of Turku, FI-20520 Turku, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Su\u00e1rez-Calvet","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain"},{"name":"IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain"},{"name":"Servei de Neurologia, Hospital del Mar, Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, 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Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Sch\u00f6ll","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden"},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden"},{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"2021052612324881800_awaa399-B1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41582-020-0348-0","article-title":"An update on blood-based biomarkers 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