title: Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.
abstract: In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 3 UCL Institute of Neurology, Department of Molecular Neuroscience, Queen Square, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: 4 Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Argonde C
authors.initials: AC
authors.lastname: van Harten
authors.affiliation: 5 Centre for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Glodzik
authors.affiliation: 6 Department of Neurology, Centre for Research and Advanced Therapies. Fundación CITA-Alzheimer Fundazioa, Donostia/San Sebastián, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martinez-Lage
authors.affiliation: 7 IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy 8 Faculty of Psychology, eCampus University, Novedrate (Como), Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Bocchio-Chiavetto
authors.affiliation: 9 Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic i Universitari, Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rami
authors.affiliation: 10 Department of Clinical Sciences, Lund University, Lund, Sweden 11 Memory clinic, Skåne University Hospital, Lund, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: 11 Memory clinic, Skåne University Hospital, Lund, Sweden.
authors.forename: Reisa
authors.initials: R
authors.lastname: Sperling
authors.affiliation: 13 Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Belgium 14 Reference Centre for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: 5 Centre for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, USA.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Osorio
authors.affiliation: 15 ADx NeuroSciences, Technologiepark 4, Gent, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vanderstichele
authors.affiliation: 16 Fujirebio Europe nv, Technologiepark 6, Gent, Belgium.
authors.forename: Manu
authors.initials: M
authors.lastname: Vandijck
authors.affiliation: 17 AXA Research Fund and UPMC, Université Pierre et Marie Curie, Paris, France 18 Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) & Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpétrière, Paris, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.affiliation: 19 Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany 20 DZNE, German Centre for Neurodegenerative Diseases, Rostock, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Teipl
authors.affiliation: 21 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Abhay
authors.initials: A
authors.lastname: Moghekar
authors.affiliation: 21 Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
authors.affiliation: 22 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.affiliation: 23 Department of Neurology, University General Hospital of Alicante, Alicante, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Monge Argilés
authors.affiliation: 24 Neuroscience Unit, Biodonostia Research Institute, San Sebastian, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gorostidi
authors.affiliation: 25 Neurochemistry Lab and Biobank, Dept. of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Centre Amsterdam, The Netherlands.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: 13 Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Belgium 14 Reference Centre for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: 12 Massachusetts Alzheimer's Disease Research Centre, Harvard Aging Brain Study, Department of Neurology; Massachusetts General Hospital, Harvard Medical School, Boston, MA,USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: 9 Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic i Universitari, Barcelona, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: 7 IRCCS Centro San Giovanni di Dio FBF, Brescia, Italy 26 University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.affiliation: 6 Department of Neurology, Centre for Research and Advanced Therapies. Fundación CITA-Alzheimer Fundazioa, Donostia/San Sebastián, Spain.
authors.forename: Gurutz
authors.initials: G
authors.lastname: Linazasoro
authors.affiliation: 5 Centre for Brain Health, Department of Psychiatry, New York University School of Medicine, New York, USA.
authors.forename: Mony J
authors.initials: MJ
authors.lastname: de Leon
authors.affiliation: 4 Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands 27 Department of Epidemiology/Biostatistics, VU University Medical Centre, USA.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: 4 Alzheimer Centre and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 27 Department of Epidemiology/Biostatistics, VU University Medical Centre, USA.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, Institute on Aging, Centre for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA trojanow@mail.med.upenn.edu.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000209:etiology; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D012720:Severity of Illness Index; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; biomarkers; cognitive ageing; dementia; imaging