Ronald Lautner1, Sebastian Palmqvist2, Niklas Mattsson3, Ulf Andreasson1, Anders Wallin1, Erik Pålsson1, Joel Jakobsson1, Sanna-Kaisa Herukka4, Rikard Owenius5, Bob Olsson1, Harald Hampel6, Dan Rujescu7, Michael Ewers8, Mikael Landén9, Lennart Minthon2, Kaj Blennow1, Henrik Zetterberg10, Oskar Hansson2. 1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden. 2. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden3Memory Clinic, Skåne University Hospital, Malmö, Sweden. 3. 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. 4. Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland. 5. GE Healthcare, Life Sciences, Uppsala, Sweden. 6. Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Université Pierre et Marie Curie, Paris, France. 7. Department of Psychiatry, University of Halle, Halle, Germany. 8. Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California. 9. 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. 10. 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.
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.
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.
Authors: Jon B Toledo; Henrik Zetterberg; Argonde C van Harten; Lidia Glodzik; Pablo Martinez-Lage; Luisella Bocchio-Chiavetto; Lorena Rami; Oskar Hansson; Reisa Sperling; Sebastiaan Engelborghs; Ricardo S Osorio; Hugo Vanderstichele; Manu Vandijck; Harald Hampel; Stefan Teipl; Abhay Moghekar; Marilyn Albert; William T Hu; Jose A Monge Argilés; Ana Gorostidi; Charlotte E Teunissen; Peter P De Deyn; Bradley T Hyman; Jose L Molinuevo; Giovanni B Frisoni; Gurutz Linazasoro; Mony J de Leon; Wiesje M van der Flier; Philip Scheltens; Kaj Blennow; Leslie M Shaw; John Q Trojanowski Journal: Brain Date: 2015-07-27 Impact factor: 13.501
Authors: Michael W Weiner; Dallas P Veitch; Paul S Aisen; Laurel A Beckett; Nigel J Cairns; Robert C Green; Danielle Harvey; Clifford R Jack; William Jagust; John C Morris; Ronald C Petersen; Andrew J Saykin; Leslie M Shaw; Arthur W Toga; John Q Trojanowski Journal: Alzheimers Dement Date: 2017-03-22 Impact factor: 21.566
Authors: Yuetiva Deming; Fabia Filipello; Francesca Cignarella; Claudia Cantoni; Simon Hsu; Robert Mikesell; Zeran Li; Jorge L Del-Aguila; Umber Dube; Fabiana Geraldo Farias; Joseph Bradley; John Budde; Laura Ibanez; Maria Victoria Fernandez; Kaj Blennow; Henrik Zetterberg; Amanda Heslegrave; Per M Johansson; Johan Svensson; Bengt Nellgård; Alberto Lleo; Daniel Alcolea; Jordi Clarimon; Lorena Rami; José Luis Molinuevo; Marc Suárez-Calvet; Estrella Morenas-Rodríguez; Gernot Kleinberger; Michael Ewers; Oscar Harari; Christian Haass; Thomas J Brett; Bruno A Benitez; Celeste M Karch; Laura Piccio; Carlos Cruchaga Journal: Sci Transl Med Date: 2019-08-14 Impact factor: 17.956
Authors: Jonathan Spiegel; Elizabeth Pirraglia; Ricardo S Osorio; Lidia Glodzik; Yi Li; Wai Tsui; Leslie A Saint Louis; Catherine Randall; Tracy Butler; Jinfeng Xu; Raymond P Zinkowski; Henrik Zetterberg; Juan Fortea; Silvia Fossati; Thomas Wisniewski; Peter Davies; Kaj Blennow; Mony J de Leon Journal: J Alzheimers Dis Date: 2016 Impact factor: 4.472