Silvia Ingala1,2, Casper De Boer2, Larissa A Masselink2, Ilaria Vergari1,2, Luigi Lorenzini1, Kaj Blennow3,4, Gaël Chételat5, Carol Di Perri6, Michael Ewers7, Wiesje M van der Flier2, Nick C Fox8, Juan Domingo Gispert9,10,11, Sven Haller12, José Luís Molinuevo9,13, Graciela Muniz-Terrera6, Henri Jmm Mutsaerts1,14, Craig W Ritchie15, Karen Ritchie15, Mark Schmidt16, Adam J Schwarz17, Lisa Vermunt2, Adam D Waldman6,15, Joanna Wardlaw6,15, Alle Meije Wink1, Robin Wolz18, Viktor Wottschel1, Philip Scheltens2, Pieter Jelle Visser2,19, Frederik Barkhof1,20. 1. Department of Radiology and Nuclear Medicine, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands. 2. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands. 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. 4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 5. Normandie Univ, UNICAEN, INSERM, U1237, PhIND "Physiopathology and Imaging of Neurological Disorders,", Institut Blood and Brain @ Caen-Normandie, Cyceron, Caen, France. 6. Centre for Dementia Prevention, Edinburgh Imaging, UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK. 7. Institute for Stroke and Dementia Research, Klinikum der Universitat München, Ludwig-Maximilians-Universitat LMU, Munich, Germany. 8. Dementia Research Centre, Department of Neurodegenerative Disease & UK Dementia Research Institute, Institute of Neurology, University College London, London, UK. 9. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. 10. CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. 11. Universitat Pompeu Fabra, Barcelona, Spain. 12. CIRD Centre d'Imagerie Rive Droite, Geneva, Switzerland. 13. Hopsital Clínic-IDIBAPS, Alzheimer's Disease & Other Cognitive Disorders Unit, Barcelona, Spain. 14. Ghent Institute for Functional and Metabolic Imaging (GIfMI), Ghent University, Ghent, Belgium. 15. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 16. Janssen Pharmaceutica NV, Beerse, Belgium. 17. Takeda Pharmaceutical Company Ltd, Cambridge, Massachusetts, USA. 18. IXICO Plc, London, UK. 19. Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. 20. Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
Abstract
BACKGROUND: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. MATERIALS AND METHODS: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. RESULTS: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001). DISCUSSION: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
BACKGROUND: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. MATERIALS AND METHODS: From 1500 EPADparticipants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. RESULTS: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001). DISCUSSION: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
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