Marta Milà-Alomà1,2,3,4, Gemma Salvadó1,2, Juan Domingo Gispert1,2,3,5, Natalia Vilor-Tejedor1,3,6,7, Oriol Grau-Rivera1,2,4,8, Aleix Sala-Vila1,2, Gonzalo Sánchez-Benavides1,2,4, Eider M Arenaza-Urquijo1,2,4, Marta Crous-Bou1,2,4,9, José Maria González-de-Echávarri1,2, Carolina Minguillon1,2,4, Karine Fauria1,4, Maryline Simon10, Gwendlyn Kollmorgen11, Henrik Zetterberg12,13,14,15, Kaj Blennow12,13, Marc Suárez-Calvet1,2,4,8, José Luis Molinuevo1,2,3,4. 1. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. 2. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 3. Universitat Pompeu Fabra, Barcelona, Spain. 4. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. 5. Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain. 6. Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain. 7. Department of Clinical Genetics, ERASMUS MC, Rotterdam, the Netherlands. 8. Servei de Neurologia, Hospital del Mar, Barcelona, Spain. 9. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 10. Roche Diagnostics International Ltd, Rotkreuz, Switzerland. 11. Roche Diagnostics GmbH, Penzberg, Germany. 12. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden. 13. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 14. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom. 15. UK Dementia Research Institute at UCL, London, United Kingdom.
Abstract
INTRODUCTION: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. METHODS: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. RESULTS: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. DISCUSSION: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
INTRODUCTION: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. METHODS: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. RESULTS: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. DISCUSSION: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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