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A Cluster of Cholesterol-Related Genes Confers Susceptibility for Alzheimer's Disease

Andreas Papassotiropoulos, M.D.; M. Axel Wollmer, M.D.; Magdalini Tsolaki, M.D.; Fabienne Brunner, M.Sc.; Dimitra Molyva, M.Sc.; Dieter Lütjohann, Ph.D.; Roger M. Nitsch, M.D.; and Christoph Hock, M.D.

Objective: Polygenic diseases are related to the complex interplay of genetic variations. We evaluated whether clusters of cholesterol- and lipid-related genetic variations are associated with Alzheimer's disease.

Method: We analyzed 12 cholesterol-related single nucleotide polymorphisms and 48 control polymorphisms in 545 study participants (Alzheimer's disease group N = 284; control group N = 261). Diagnoses of Alzheimer's disease were made according to the NINCDS-ADRDA criteria. Multi-locus genetic association analysis was done with the set-association method. Dates of data collection were from January 2000 to December 2003.

Results: We identified a cluster of polymorphisms in APOE, SOAT1, APOE 5'-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4 conferring significant (p = .0002) susceptibility for Alzheimer's disease. This gene cluster reached a diagnostic accuracy of 74% and correlated significantly (p = .018) with the levels of the brain cholesterol catabolite 24S-hydroxycholesterol in the cerebrospinal fluid.

Conclusion: Our results establish a novel approach for the identification of disease-related genetic clusters and demonstrate the need for multi-locus methods in the genetics of complex diseases.

(J Clin Psychiatry 2005;66:940-947)

Received Feb. 4, 2005; accepted April 21, 2005. From the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland (Drs. Papassotiropoulos, Wollmer, Nitsch, and Hock and Ms. Brunner); the Third Department of Neurology, Aristotle University of Thessaloniki, Greece (Dr. Tsolaki and Ms. Molyva); and the Department of Clinical Pharmacology, University of Bonn, Bonn, Germany (Dr. Lütjohann).

Supported by grants from the Swiss National Science Foundation (PP00B-68859) and the EMDO-Stiftung (Dr. Papassotiropoulos), by the EU DIADEM (Early DIagnosis of Alzheimer's disease and related DEMentia) program, and by the National Center for Competence in Research (NCCR) "Neuronal Plasticity and Repair,"Switzerland.

The authors report no other financial affiliation or other relationship relevant to the subject matter of this article.

The authors thank Esmeralda Garcia, Christin Wilde, and Andrea Walther of the Division of Psychiatry Research for excellent clinical study support and Dominique de Quervain, M.D., of the Division of Psychiatry Research for careful manuscript reading.

Corresponding author and reprints: Andreas Papassotiropoulos, M.D., Division of Psychiatry Research, University of Zürich, Lenggstrasse 31, 8029 Zürich, Switzerland (e-mail: