title: Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.
authors.affiliation: Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. papas@bli@unizh.ch
authors.forename: Andreas
authors.initials: A
authors.lastname: Papassotiropoulos
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Fabienne
authors.initials: F
authors.lastname: Wavrant-De Vrièze
authors.forename: M Axel
authors.initials: MA
authors.lastname: Wollmer
authors.forename: Heinz
authors.initials: H
authors.lastname: von der Kammer
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Streffer
authors.forename: Alessia
authors.initials: A
authors.lastname: Maddalena
authors.forename: Kim-Dung
authors.initials: KD
authors.lastname: Huynh
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wolleb
authors.forename: Dieter
authors.initials: D
authors.lastname: Lutjohann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schneider
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Luigi M E
authors.initials: LM
authors.lastname: Grimaldi
authors.forename: Magdalini
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kapaki
authors.forename: Rivka
authors.initials: R
authors.lastname: Ravid
authors.forename: Uwe
authors.initials: U
authors.lastname: Konietzko
authors.forename: Thomas
authors.initials: T
authors.lastname: Hegi
authors.forename: Thomas
authors.initials: T
authors.lastname: Pasch
authors.forename: Hans
authors.initials: H
authors.lastname: Jung
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Rogaev
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Christoph
authors.initials: C
authors.lastname: Hock
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D016229:Amyloid beta-Peptides; D005819:Genetic Markers; D012333:RNA, Messenger; C001521:lathosterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase