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Original Investigation
October 2014

Apolipoprotein E Genotype and the Diagnostic Accuracy of Cerebrospinal Fluid Biomarkers for Alzheimer Disease

Author Affiliations
  • 1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden
  • 2Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
  • 3Memory Clinic, Skåne University Hospital, Malmö, Sweden
  • 4Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California
  • 5Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
  • 6GE Healthcare, Life Sciences, Uppsala, Sweden
  • 7Département de Neurologie, Institut de la Mémoire et de la Maladie d’Alzheimer, Université Pierre et Marie Curie, Paris, France
  • 8Department of Psychiatry, University of Halle, Halle, Germany
  • 9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 10Institute of Neurology, University College of London, London, England
JAMA Psychiatry. 2014;71(10):1183-1191. doi:10.1001/jamapsychiatry.2014.1060

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.