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Increased Brain  -Amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated With an Intronic CYP46 Polymorphism
Andreas Papassotiropoulos, MD;
Johannes R. Streffer, MD;
Magdalini Tsolaki, MD;
Simon Schmid, MD;
Dietmar Thal, MD;
Francesca Nicosia, PhD;
Vassiliki Iakovidou, MD;
Alessia Maddalena, MD;
Dieter Lütjohann, PhD;
Estifanos Ghebremedhin, MD;
Thomas Hegi, MD;
Thomas Pasch, MD;
Muriel Träxler, BSc;
Annette Brühl, MD;
Luisa Benussi, PhD;
Giuliano Binetti, MD;
Heiko Braak, MD;
Roger M. Nitsch, MD;
Christoph Hock, MD
Arch Neurol. 2003;60:29-35.
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 ( -amyloid load, -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 -amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of -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  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 4 alone (95% CI, 2.8-6.8; P<.001).
Conclusion CYP46 influences brain -amyloid load, cerebrospinal fluid levels of -amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.
From the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland (Drs Papassotiropoulos, Streffer, Schmid, Maddalena, Brühl, Nitsch, and Hock and Ms Träxler); Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece (Drs Tsolaki and Iakovidou); Institute of Anatomy, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany (Drs Thal, Ghebremedhin, and Braak); Neurobiology Laboratory, Instituto di Ricovero e Cura a Carattere Scientifico Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy (Drs Nicosia, Benussi, and Binetti); Institute for Clinical Pharmacology, University of Bonn, Bonn, Germany (Dr Lütjohann); and Institute for Anesthesiology, University of Zurich, Zurich, Switzerland (Drs Hegi and Pasch).
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