title: Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.
abstract: Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lacour
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Espinosa
authors.affiliation: Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Louwersheimer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Hernández
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wolfsgruber
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Fernández
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rosende-Roca
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Mauleón
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Moreno-Grau
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Vargas
authors.affiliation: Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Y A L
authors.initials: YA
authors.lastname: Pijnenburg
authors.affiliation: Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Koene
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Rodríguez-Gómez
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Ortega
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ruiz
authors.affiliation: Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Holstege
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Sotolongo-Grau
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry, Charité University Medicine, Berlin, Germany.
authors.forename: O
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: L
authors.initials: L
authors.lastname: Frölich
authors.affiliation: Center for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Rüther
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Scherer
authors.affiliation: Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Riedel-Heller
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alegret
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Tárraga
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.|Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Jessen
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Boada
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: W M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ruiz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers; D051152:Clusterin / Q000235:genetics; D060825:Cognitive Dysfunction / Q000235:genetics; D003704:Dementia / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D053327:Apolipoprotein E4; D015415:Biomarkers; C495242:CLU protein, human; D051152:Clusterin