title: Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.
abstract: BACKGROUND
  Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.
  
  
  METHODS
  We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.
  
  
  RESULTS
  We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.
  
  
  CONCLUSIONS
  Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
authors.affiliation: Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom.
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: Peter A
authors.initials: PA
authors.lastname: Holmans
authors.forename: Marian L
authors.initials: ML
authors.lastname: Hamshere
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Dobril
authors.initials: D
authors.lastname: Ivanov
authors.forename: Andrew
authors.initials: A
authors.lastname: Pocklington
authors.forename: Richard
authors.initials: R
authors.lastname: Abraham
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sims
authors.forename: Amy
authors.initials: A
authors.lastname: Gerrish
authors.forename: Jaspreet Singh
authors.initials: JS
authors.lastname: Pahwa
authors.forename: Nicola
authors.initials: N
authors.lastname: Jones
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stretton
authors.forename: Angharad R
authors.initials: AR
authors.lastname: Morgan
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Petroula
authors.initials: P
authors.lastname: Proitsi
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Lupton
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Brian
authors.initials: B
authors.lastname: Lawlor
authors.forename: Aoibhinn
authors.initials: A
authors.lastname: Lynch
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Kristelle S
authors.initials: KS
authors.lastname: Brown
authors.forename: Peter A
authors.initials: PA
authors.lastname: Passmore
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.forename: Bernadette
authors.initials: B
authors.lastname: McGuinness
authors.forename: Stephen
authors.initials: S
authors.lastname: Todd
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Nick
authors.initials: N
authors.lastname: Fox
authors.forename: Martin
authors.initials: M
authors.lastname: Rossor
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.forename: Britta
authors.initials: B
authors.lastname: Schürmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Heike
authors.initials: H
authors.lastname: Kölsch
authors.forename: Hendrik
authors.initials: H
authors.lastname: van den Bussche
authors.forename: Isabella
authors.initials: I
authors.lastname: Heuser
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Lutz
authors.initials: L
authors.lastname: Frölich
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Gill
authors.initials: G
authors.lastname: Livingston
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bass
authors.forename: Hugh
authors.initials: H
authors.lastname: Gurling
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Eckhard
authors.initials: E
authors.lastname: Rüther
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007107:Immune System / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: D001057:Apolipoproteins E; D002784:Cholesterol