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Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease

Molecular Psychiatry volume 7, pages 899–902 (2002)Cite this article

Abstract

Cholesterol and 24S-hydroxycholesterol are involved in the pathogenesis of Alzheimer's disease (AD). Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24S-hydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C → T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A → G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C → T polymorphism was associated with an increased 24S-hydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain.

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Acknowledgements

We thank Sandra Schmitz, Anja Kerksiek and Christian Ehl for technical assistance. This study was supported by grants of the Deutsche Forschungsgemeinschaft (HE2318/1–1, 1–2), of the Alzheimer Association (IIRG98–142) and of the Bundesministerium für Bildung und Forschung (01EC9402).

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  1. H Kölsch and D Lütjohann: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Psychiatry, University of Bonn, Bonn, Germany

    H Kölsch, A Schulte, U Ptok, F Jessen, M L Rao, W Maier & R Heun

  2. Clinical Pharmacology, University of Bonn, Bonn, Germany

    D Lütjohann & K von Bergmann

  3. Clinical Biochemistry, University of Bonn, Bonn, Germany

    M Ludwig

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  1. H Kölsch
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  2. D Lütjohann
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Correspondence to H Kölsch.

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Kölsch, H., Lütjohann, D., Ludwig, M. et al. Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease. Mol Psychiatry 7, 899–902 (2002). https://doi.org/10.1038/sj.mp.4001109

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