Increased brain {beta}-amyloid load, phosphorylated tau, and risk of Alzheimer Disease associated with an intronic CYP46 polymorphism

Papassotiropoulos, Andreas, Streffer, Johannes R., Tsolaki, Magdalini, Schmid, Simon, Thal, Dietmar, Nicosia, Francesca, Iakovidou, Vassiliki, Maddalena, Alessia, Lütjohann, Dieter, Ghebremedhin, Estifanos, Hegi, Thomas, Pasch, Thomas, Träxler, Muriel, Brühl, Annette, Benussi, Luisa, Binetti, Giuliano, Braak, Heiko, Nitsch, Roger M. and Hock, Christoph (2003) Increased brain {beta}-amyloid load, phosphorylated tau, and risk of Alzheimer Disease associated with an intronic CYP46 polymorphism. JAMA Neurology, 60 1: 29-35. doi:10.1001/archneur.60.1.29

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Author Papassotiropoulos, Andreas
Streffer, Johannes R.
Tsolaki, Magdalini
Schmid, Simon
Thal, Dietmar
Nicosia, Francesca
Iakovidou, Vassiliki
Maddalena, Alessia
Lütjohann, Dieter
Ghebremedhin, Estifanos
Hegi, Thomas
Pasch, Thomas
Träxler, Muriel
Brühl, Annette
Benussi, Luisa
Binetti, Giuliano
Braak, Heiko
Nitsch, Roger M.
Hock, Christoph
Title Increased brain {beta}-amyloid load, phosphorylated tau, and risk of Alzheimer Disease associated with an intronic CYP46 polymorphism
Journal name JAMA Neurology   Check publisher's open access policy
ISSN 2168-6149
2168-6157
Publication date 2003-01
Year available 2003
Sub-type Article (original research)
DOI 10.1001/archneur.60.1.29
Open Access Status File (Publisher version)
Volume 60
Issue 1
Start page 29
End page 35
Total pages 7
Place of publication Chicago, IL, United States
Publisher American Medical Association
Language eng
Formatted abstract
Background
CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain.

Objective To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD.

Design
Alzheimer disease traits ({beta}-amyloid load, {beta}-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations.

Setting
Specialized centers for memory disorders in Switzerland, Greece, and Italy.

Participants
Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies.

Results
A polymorphism of CYP46 was associated with increased {beta}-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of {beta}-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E {epsilon}4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E {epsilon}4 alone (95% CI, 2.8-6.8; P<.001).

Conclusion
CYP46 influences brain {beta}-amyloid load, cerebrospinal fluid levels of {beta}-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.
Keyword Cholesterol
24-hydroxylase
Polymorphic sites
CYP46
Alzheimer Disease
Development
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Biomedical Sciences Publications
 
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Created: Tue, 08 Dec 2009, 11:09:19 EST by Macushla Boyle on behalf of Faculty of Science