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Mol Psychiatry. 2017 Jan;22(1):153-160. doi: 10.1038/mp.2016.18. Epub 2016 Mar 15.

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.

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
2
Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
3
Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
4
Institute of Human Genetics, University of Bonn, Bonn, Germany.
5
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
6
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
7
Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
8
Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
9
Department of Psychiatry, Charité University Medicine, Berlin, Germany.
10
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
11
Center for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
12
Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
13
Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
14
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
15
Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany.
16
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
17
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

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.

PMID:
26976043
PMCID:
PMC5414086
DOI:
10.1038/mp.2016.18
[Indexed for MEDLINE]
Free PMC Article

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