title: The screening of Alzheimer's patients with CSF biomarkers, modulates the distribution of APOE genotype: impact on clinical trials.
abstract: Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer's disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1-42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1-42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1-42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.
authors.affiliation: Memory Clinical Center CMRR Paris Nord Ile-de-France, Saint Louis-Lariboisiere, Fernand Widal Hospital, AP-HP, University Paris 7-Denis Diderot, Paris, France, julien.dumurgier@inserm.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Dumurgier
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.forename: Francois
authors.initials: F
authors.lastname: Mouton-Liger
authors.forename: Pauline
authors.initials: P
authors.lastname: Lapalus
authors.forename: Sandrine
authors.initials: S
authors.lastname: Indart
authors.forename: Magali
authors.initials: M
authors.lastname: Prévot
authors.forename: Katell
authors.initials: K
authors.lastname: Peoc'h
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D012372:ROC Curve; D012189:Retrospective Studies
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
references.citation: Acta Neuropathol. 2009 Jul;118(1):5-36
references.pmid: 19381658
references.citation: JAMA. 1997 Oct 22-29;278(16):1349-56
references.pmid: 9343467
references.citation: Dement Geriatr Cogn Disord. 2005;20(4):254-61
references.pmid: 16103669
references.citation: Alzheimers Dement. 2013 May;9(3):251-61
references.pmid: 23622690
references.citation: Neurology. 2009 Dec 15;73(24):2061-70
references.pmid: 19923550
references.citation: Alzheimers Dement. 2013 Jul;9(4):406-13
references.pmid: 23141384
references.citation: Alzheimers Dement. 2011 May;7(3):263-9
references.pmid: 21514250
references.citation: J Neurol. 2014 Jan;261(1):144-51
references.pmid: 24162039
references.citation: Arch Gen Psychiatry. 2012 Jan;69(1):98-106
references.pmid: 22213792
references.citation: Neurobiol Aging. 1998 Mar-Apr;19(2):109-16
references.pmid: 9558143
references.citation: Neurobiol Aging. 2000 Sep-Oct;21(5):735-40
references.pmid: 11016543
references.citation: Lancet Neurol. 2012 Mar;11(3):241-9
references.pmid: 22305802
references.citation: Nat Rev Neurol. 2010 Mar;6(3):131-44
references.pmid: 20157306
references.citation: Stat Med. 2008 Jan 30;27(2):157-72; discussion 207-12
references.pmid: 17569110
references.citation: Neurobiol Aging. 2013 Jan;34(1):1-12
references.pmid: 22633529
references.citation: Lancet Neurol. 2007 Aug;6(8):734-46
references.pmid: 17616482
references.citation: J Alzheimers Dis. 2009;16(3):601-7
references.pmid: 19276554
references.citation: Curr Alzheimer Res. 2013 May 1;10(4):357-64
references.pmid: 23061918
references.citation: Ann Clin Biochem. 2009 May;46(Pt 3):235-40
references.pmid: 19342441
references.citation: Pharmacogenetics. 2002 Jul;12(5):415-20
references.pmid: 12142731
references.citation: Curr Neurol Neurosci Rep. 2012 Jun;12(3):243-50
references.pmid: 22477152
references.citation: Nat Rev Neurol. 2013 Feb;9(2):106-18
references.pmid: 23296339
references.citation: Lancet Neurol. 2010 Nov;9(11):1118-27
references.pmid: 20934914
references.citation: J Neurochem. 2007 May;101(4):1053-9
references.pmid: 17254013
references.citation: Ann Neurol. 2010 Mar;67(3):308-16
references.pmid: 20373342
references.citation: Lancet Neurol. 2011 Mar;10(3):241-52
references.pmid: 21349439
references.citation: J Neurol Sci. 2014 Jan 15;336(1-2):103-8
references.pmid: 24189208
references.citation: Arch Neurol. 1998 Jul;55(7):964-8
references.pmid: 9678314
references.citation: J Alzheimers Dis. 2013;36(4):759-67
references.pmid: 23666174
references.citation: Biol Psychiatry. 2010 Nov 15;68(10):879-84
references.pmid: 20598287
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Dement Geriatr Cogn Disord. 2002;14(4):183-90
references.pmid: 12411760
references.citation: Neurology. 2004 Jun 8;62(11):2116-8
references.pmid: 15184629
references.citation: Lancet Neurol. 2008 Aug;7(8):668-70
references.pmid: 18635012
references.citation: Neurology. 2012 Jan 3;78(1):47-54
references.pmid: 22170879
references.citation: Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712
references.pmid: 21852788
references.citation: Neurology. 2001 Jun 26;56(12):1696-701
references.pmid: 11425936
references.citation: Clin Chem Lab Med. 2005;43(5):512-8
references.pmid: 15899673
references.citation: Stat Med. 2011 Jan 15;30(1):11-21
references.pmid: 21204120
references.citation: Neurology. 2003 Jan 28;60(2):246-52
references.pmid: 12552039
references.citation: CNS Drugs. 2010 Feb;24(2):163-76
references.pmid: 20088621
references.citation: Nat Rev Drug Discov. 2013 Apr;12(4):324
references.pmid: 23493086
references.citation: Neurology. 2000 May 9;54(9):1875-6
references.pmid: 10802808
references.citation: N Engl J Med. 2013 Mar 28;368(13):1169-71
references.pmid: 23484795