title: Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
abstract: OBJECTIVE
  Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown.
  
  
  OBJECTIVE
  To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular Aβ42 levels, and whether the association of APOE ε4 with CSF biomarkers depends on cortical Aβ status.
  
  
  METHODS
  We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([18F]flumetamol) positron emission tomography amyloid imaging and CSF tap.
  
  
  METHODS
  Standard care.
  
  
  METHODS
  Cerebrospinal fluid levels of Aβ42 and total and phosphorylated tau in relation to the APOE ε2/ε3/ε4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [18F]flutemetamol.
  
  
  RESULTS
  The CSF levels of Aβ42 but not total and phosphorylated tau were lower in APOE ε4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of Aβ42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of Aβ42 and APOE ε4 genotype were independent predictors of AD diagnosis. In cohort B, APOE ε4 carrier status did not influence CSF levels of Aβ42. Moreover, when stratifying for cortical uptake of [18F]flutemetamol in cohort C, APOE ε4 genotype did not influence CSF levels of Aβ42. This result was replicated in a cohort with individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning.
  
  
  CONCLUSIONS
  Cerebrospinal fluid levels of Aβ42 are strongly associated with the diagnosis of AD and cortical Aβ accumulation independent of APOE genotype. The clinical cutoff for CSF levels of Aβ42 should be the same for all APOE genotypes.
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lautner
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Palmqvist
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden4Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical C.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Wallin
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Pålsson
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Jakobsson
authors.affiliation: Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: GE Healthcare, Life Sciences, Uppsala, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Owenius
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Bob
authors.initials: B
authors.lastname: Olsson
authors.affiliation: Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Université Pierre et Marie Curie, Paris, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sw.
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden10Institute of Neurology, University College of London, London, England.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D015203:Reproducibility of Results; D055815:Young Adult; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins