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Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.

Abstract

IMPORTANCE

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.

DESIGN, SETTING, AND PARTICIPANTS

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.

EXPOSURES

Standard care.

MAIN OUTCOMES AND MEASURES

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 AND RELEVANCE

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.

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  • Publisher Full Text
  • Authors+Show Affiliations

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.

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    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.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.

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    GE Healthcare, Life Sciences, Uppsala, Sweden.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Université Pierre et Marie Curie, Paris, France.

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    Department of Psychiatry, University of Halle, Halle, Germany.

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    Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California.

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    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.

    ,

    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.

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    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden.

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    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.

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    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden.

    Source

    JAMA psychiatry 71:10 2014 Oct pg 1183-91

    MeSH

    Adult
    Aged
    Aged, 80 and over
    Alleles
    Alzheimer Disease
    Amyloid beta-Peptides
    Apolipoprotein E4
    Apolipoproteins E
    Biomarkers
    Cognitive Dysfunction
    Dementia
    Female
    Genotype
    Humans
    Male
    Middle Aged
    Peptide Fragments
    Reproducibility of Results
    Young Adult
    tau Proteins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25162367

    Citation

    Lautner, Ronald, et al. "Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease." JAMA Psychiatry, vol. 71, no. 10, 2014, pp. 1183-91.
    Lautner R, Palmqvist S, Mattsson N, et al. Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease. JAMA Psychiatry. 2014;71(10):1183-91.
    Lautner, R., Palmqvist, S., Mattsson, N., Andreasson, U., Wallin, A., Pålsson, E., ... Hansson, O. (2014). Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease. JAMA Psychiatry, 71(10), pp. 1183-91. doi:10.1001/jamapsychiatry.2014.1060.
    Lautner R, et al. Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease. JAMA Psychiatry. 2014;71(10):1183-91. PubMed PMID: 25162367.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease. AU - Lautner,Ronald, AU - Palmqvist,Sebastian, AU - Mattsson,Niklas, AU - Andreasson,Ulf, AU - Wallin,Anders, AU - Pålsson,Erik, AU - Jakobsson,Joel, AU - Herukka,Sanna-Kaisa, AU - Owenius,Rikard, AU - Olsson,Bob, AU - Hampel,Harald, AU - Rujescu,Dan, AU - Ewers,Michael, AU - Landén,Mikael, AU - Minthon,Lennart, AU - Blennow,Kaj, AU - Zetterberg,Henrik, AU - Hansson,Oskar, AU - ,, PY - 2014/8/28/entrez PY - 2014/8/28/pubmed PY - 2014/12/17/medline SP - 1183 EP - 91 JF - JAMA psychiatry JO - JAMA Psychiatry VL - 71 IS - 10 N2 - IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Standard care. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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. SN - 2168-6238 UR - https://www.unboundmedicine.com/medline/citation/25162367/Apolipoprotein_E_genotype_and_the_diagnostic_accuracy_of_cerebrospinal_fluid_biomarkers_for_Alzheimer_disease_ L2 - https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2014.1060 DB - PRIME DP - Unbound Medicine ER -