Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease.
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.
Papassotiropoulos
Andreas
A
Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. papas@bli@unizh.ch
Lambert
Jean-Charles
JC
Wavrant-De Vrièze
Fabienne
F
Wollmer
M Axel
MA
von der Kammer
Heinz
H
Streffer
Johannes R
JR
Maddalena
Alessia
A
Huynh
Kim-Dung
KD
Wolleb
Sibylle
S
Lutjohann
Dieter
D
Schneider
Brigitte
B
Thal
Dietmar R
DR
Grimaldi
Luigi M E
LM
Tsolaki
Magdalini
M
Kapaki
Elisabeth
E
Ravid
Rivka
R
Konietzko
Uwe
U
Hegi
Thomas
T
Pasch
Thomas
T
Jung
Hans
H
Braak
Heiko
H
Amouyel
Philippe
P
Rogaev
Evgeny I
EI
Hardy
John
J
Hock
Christoph
C
Nitsch
Roger M
RM
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*
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