title: Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment.
abstract: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI).
  
  
  
  We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau).
  
  
  
  PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)).
  
  
  
  In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.
authors.affiliation: Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands. Electronic address: e.louwersheimer@vumc.nl.
authors.forename: Eva
authors.initials: E
authors.lastname: Louwersheimer
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wolfsgruber
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Espinosa
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lacour
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann-Heimbach
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Alegret
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Maitée
authors.initials: M
authors.lastname: Rosende-Roca
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Tárraga
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry, Charité University Medicine, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Frölich
authors.affiliation: Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rüther
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Scherer
authors.affiliation: Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Riedel-Heller
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Alzheimer Center and Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ted
authors.initials: T
authors.lastname: Koene
authors.affiliation: Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Henne
authors.initials: H
authors.lastname: Holstege
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany. Electronic address: alfredo.ramirez@ukb.uni-bonn.de.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000150:complications* / Q000235:genetics; D015331:Cohort Studies; D066264:Datasets as Topic / Q000706:statistics & numerical data; D058068:Endophenotypes / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D009483:Neuropsychological Tests; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018709:Statistics, Nonparametric
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E
keywords: Alzheimer's disease; Endophenotypes; Genetic risk variants; Mild cognitive impairment; Polygenic risk score