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CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

Published online by Cambridge University Press:  16 April 2020

Heike Kölsch ,
Dieter Lütjohann ,
Frank Jessen ,
Julius Popp ,
Frank Hentschel ,
Peter Kelemen ,
Sandra Schmitz ,
Wolfgang Maier  and
Reinhard Heun
Heike Kölsch*
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Dieter Lütjohann
Affiliation:
Institute of Clinical Biochemistry and Pharmacology, University of Bonn, Germany
Frank Jessen
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Julius Popp
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Frank Hentschel
Affiliation:
Division of Neuroradiology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany
Peter Kelemen
Affiliation:
Division of Neuroradiology, Central Institute of Mental Health, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany
Sandra Schmitz
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Wolfgang Maier
Affiliation:
Department of Psychiatry, University of Bonn, Germany
Reinhard Heun
Affiliation:
Division of Neuroscience, University of Birmingham, UnitedKingdom
*
*Corresponding author. Unikliniken Bonn, Klinik fur Psychiatrie und Psychotherapie, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. Tel.: +49 228 287 19398; fax: +49 228 287 16383. E-mail address: [email protected] (H. Kölsch).
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Abstract

Background

Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.

Methods

We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.

Results

Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).

Conclusion

Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

Keywords

Cholesterol 24S-hydroxylaseAlzheimer’s diseaseCSFCholesterol metabolism
Type
Original article
Information
European Psychiatry , Volume 24 , Issue 3 , April 2009 , pp. 183 - 190
Copyright
Copyright © Elsevier Masson SAS 2009

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