The cerebrospinal fluid "Alzheimer profile": easily said, but what does it mean?
BACKGROUND
We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (Aβ42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimer's disease (AD).


METHODS
We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442).


RESULTS
Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/Aβ42 ratio and 0.08 for the p-tau/Aβ42 ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/Aβ42 ratio.


CONCLUSIONS
A tau/Aβ42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: F.Duits@vumc.nl.
Flora H
FH
Duits
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Charlotte E
CE
Teunissen
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Femke H
FH
Bouwman
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, Institute of Brain and Behaviour, University of Maastricht, Maastricht, The Netherlands.
Pieter-Jelle
PJ
Visser
Department of Neurochemistry and Psychiatry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
Niklas
N
Mattsson
Department of Neurochemistry and Psychiatry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, UK.
Henrik
H
Zetterberg
Department of Neurochemistry and Psychiatry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Kaj
K
Blennow
Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
Oskar
O
Hansson
Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
Lennart
L
Minthon
KI-Alzheimer Disease Research Centre, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Niels
N
Andreasen
Division of Geriatric Medicine, Department of Neuroscience and Locomotion, Linköping University, Linköping, Sweden.
Jan
J
Marcusson
Department of Neurochemistry and Psychiatry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Anders
A
Wallin
Donders Institute for Brain Cognition and Behaviour, Radboud Alzheimer Center, Nijmegen, The Netherlands.
Marcel Olde
MO
Rikkert
Memory and Dementia Centre, 3rd Department of Neurology, Aristotle University of Thessaloniki, "G. Papanicolaou" General Hospital, Thessaloniki, Greece.
Magda
M
Tsolaki
Clinica Neurologica, University of Perugia, Perugia, Italy.
Lucilla
L
Parnetti
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Sanna-Kaisa
SK
Herukka
Département de Neurologie & Institut de la Mémoire et de la Maladie d'Alzheimer Pavillon, Université Pierre et Marie Curie, François Lhermitte Hôpital de la Salpêtrière, Paris, France.
Harald
H
Hampel
Center for Brain Health, New York University, School of Medicine, New York, NY, USA.
Mony J
MJ
De Leon
Sektion Gerontopsychiatrie, Universität Heidelberg, Heidelberg, Germany.
Johannes
J
Schröder
Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
Dag
D
Aarsland
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Marinus A
MA
Blankenstein
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Philip
P
Scheltens
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Wiesje M
WM
van der Flier
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D012372:ROC Curve; D012044:Regression Analysis; D016875:tau Proteins / Q000134:cerebrospinal fluid*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
Alzheimer's disease; Amyloid-β(1-42); Biomarkers; Cerebrospinal fluid; Dementia; Differential diagnosis; Mild cognitive impairment; Predictive value; Tau