title: Effects of Alzheimer's disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach.
abstract: BACKGROUND
  Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis.
  
  
  OBJECTIVE
  To investigate the individual and combined risk effects of the newly identified AD loci.
  
  
  METHODS
  Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex.
  
  
  RESULTS
  Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction.
  
  
  CONCLUSIONS
  AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Martiskainen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Viswanathan
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mitja
authors.initials: M
authors.lastname: Kurki
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Anette
authors.initials: A
authors.lastname: Hall
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Natunen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Kaisa M A
authors.initials: KM
authors.lastname: Kurkinen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Huovinen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Laitinen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Koivisto
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Kari M
authors.initials: KM
authors.lastname: Mattila
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; amyloid-β peptide; biomarker; cerebrospinal fluid; polygenic risk score; risk gene; tau protein