title: Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models.
abstract: Abnormalities in brains of Alzheimer's disease (AD) patients are thought to start long before the first clinical symptoms emerge. The identification of affected individuals at this 'preclinical AD' stage relies on biomarkers such as decreased levels of the amyloid-β peptide (Aβ) in the cerebrospinal fluid (CSF) and positive amyloid positron emission tomography scans. However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective. To this end, we have studied CSF Aβ changes in three Aβ precursor protein transgenic mouse models, focusing our analysis on the initial Aβ deposition, which differs significantly among the models studied. Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20-30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models. The biphasic nature of this observed biomarker changes stresses the need for longitudinal biomarker studies in the clinical setting and the search for new 'preclinical AD' biomarkers at even earlier disease stages, by using both mice and human samples. Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany Department of Neurology, Hospital de Santo António-CHP, Porto, Portugal luis.maia@medizin.uni-tuebingen.de mathias.jucker@uni-tuebingen.de.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Maia
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.affiliation: Novartis Institutes for Biomedical Research Neuroscience Discovery Basel, Basel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obermüller
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schelle
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Odenthal
authors.affiliation: Institute of Clinical Epidemiology and applied Biostatistics University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Martus
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany Novartis Institutes for Biomedical Research Neuroscience Discovery Basel, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany luis.maia@medizin.uni-tuebingen.de mathias.jucker@uni-tuebingen.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001921:Brain / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D004195:Disease Models, Animal; D042241:Early Diagnosis; D006801:Humans; D008137:Longitudinal Studies; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers
keywords: Alzheimer's disease; Aβ; CSF; biomarker; preclinical