Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum
Year: 2020
Type: article
Abstract: Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's 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's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) 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-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's 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-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β 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's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, 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-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.
Source: Brain
Institutions: Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, King's College London, South London and Maudsley NHS Foundation Trust, University of Turku, Turku PET Centre, Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center, Hospital Del Mar, Municipal Institute for Medical Research, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Hospital del Mar Research Institute, Sahlgrenska University Hospital, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,570
Funders: U.S. Department of Defense, Foundation for the National Institutes of Health, Alzheimer's Association, Bristol-Myers Squibb, Alzheimer's Drug Discovery Foundation, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, BrightFocus Foundation, AbbVie, F. Hoffmann-La Roche, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Gun och Bertil Stohnes Stiftelse, Northern California Institute for Research and Education, Demensförbundet, EU Joint Programme – Neurodegenerative Disease Research, Ministerio de Ciencia, Innovación y Universidades, European Commission, Eisai, Hjärnfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Orionin Tutkimussäätiö, Paulon Säätiö, Alzheimerfonden, Servier, H. Lundbeck A/S, IXICO, UK Dementia Research Institute, National Institutes of Health, Genentech, Canadian Institutes of Health Research, Instituto de Salud Carlos III, Wallenberg Centre for Molecular and Translational Medicine, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, H2020 European Research Council
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OpenAlex ID: W3107511586