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Abstract
Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy.
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1 the Sahlgrenska Academy at the University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Mölndal, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); Sahlgrenska University Hospital, Clinical Neurochemistry Laboratory, Mölndal, Sweden (GRID:grid.1649.a) (ISNI:0000 0000 9445 082X)
2 University Hospital of North Norway, Department of Neurology, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540); The Arctic University of Norway, Department of Psychology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234); University of Oslo, Institute of Clinical Medicine, Campus Ahus, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
3 Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain (GRID:grid.430077.7); Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); Hospital del Mar, Cognitive Decline and Movement Disorders Unit, Neurology Department, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811)
4 Wake Forest University School of Medicine, Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318)
5 Akershus University Hospital, Department of Neurology, Lørenskog, Norway (GRID:grid.411279.8) (ISNI:0000 0000 9637 455X)
6 Haugesund Hospital, Research Group for Age-Related Medicine, Haugesund, Norway (GRID:grid.413782.b); Haugesund Hospital, Department of Neuropsychology, Haugesund, Norway (GRID:grid.413782.b); University of Bergen, Department of Clinical Medicine (K1), Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443)
7 Haraldsplass Deaconess Hospital, Department of Geriatric Medicine, Bergen, Norway (GRID:grid.459576.c) (ISNI:0000 0004 0639 0732); University of Bergen, Department of Clinical Sciences, Faculty of Medicine, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443)
8 University Hospital of Trondheim, Department of Neurology and Clinical Neurophysiology, Trondheim, Norway (GRID:grid.52522.32) (ISNI:0000 0004 0627 3560); Norwegian University of Science and Technology, Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393)
9 University of Oslo, Department of Physics, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University hospital, Unit for Computational Radiology and Artificial Intelligence, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Department of Psychology, Faculty for Social Sciences, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
10 University Hospital of North Norway, Department of Neurology, Tromsø, Norway (GRID:grid.412244.5) (ISNI:0000 0004 4689 5540); The Arctic University of Norway, Department of Psychology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000 0001 2259 5234)
11 Psychology and Neuroscience King’s College London, Department of Old Age Psychiatry. Institute of psychiatry, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Centre for Age-Related Diseases, University Hospital Stavanger, Stavanger, Norway (GRID:grid.412835.9) (ISNI:0000 0004 0627 2891)
12 Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain (GRID:grid.430077.7); Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); Hospital del Mar, Cognitive Decline and Movement Disorders Unit, Neurology Department, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811); Universitat Pompeu Fabra, Department of Medicine and Life Sciences, Barcelona, Spain (GRID:grid.5612.0) (ISNI:0000 0001 2172 2676); ERA-Net on Cardiovascular Diseases (ERA-CVD) consortium, Barcelona, Spain (GRID:grid.5612.0)
13 Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); ERA-Net on Cardiovascular Diseases (ERA-CVD) consortium, Barcelona, Spain (GRID:grid.20522.37)
14 Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain (GRID:grid.430077.7); Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); Hospital del Mar, Cognitive Decline and Movement Disorders Unit, Neurology Department, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811); ERA-Net on Cardiovascular Diseases (ERA-CVD) consortium, Barcelona, Spain (GRID:grid.411142.3)
15 Bioventix Plc, Farnham, UK (GRID:grid.411142.3)
16 the Sahlgrenska Academy at the University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Mölndal, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
17 Bioventix Plc, Farnham, UK (GRID:grid.241167.7)
18 Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain (GRID:grid.430077.7); Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); ERA-Net on Cardiovascular Diseases (ERA-CVD) consortium, Barcelona, Spain (GRID:grid.20522.37); Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain (GRID:grid.7080.f) (ISNI:0000 0001 2296 0625)
19 the Sahlgrenska Academy at the University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Mölndal, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); Sahlgrenska University Hospital, Clinical Neurochemistry Laboratory, Mölndal, Sweden (GRID:grid.1649.a) (ISNI:0000 0000 9445 082X); Queen Square, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); UK Dementia Research Institute at UCL, London, UK (GRID:grid.511435.7) (ISNI:0000 0005 0281 4208); Clear Water Bay, Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China (GRID:grid.24515.37) (ISNI:0000 0004 1937 1450); University of Wisconsin-Madison, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
20 Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain (GRID:grid.430077.7); Hospital del Mar Research Institute, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); Hospital del Mar, Cognitive Decline and Movement Disorders Unit, Neurology Department, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811); Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain (GRID:grid.512892.5)
21 the Sahlgrenska Academy at the University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Mölndal, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582); University of Pittsburgh, Department of Psychiatry, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
22 University of Oslo, Institute of Clinical Medicine, Campus Ahus, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Akershus University Hospital, Department of Neurology, Lørenskog, Norway (GRID:grid.411279.8) (ISNI:0000 0000 9637 455X)