Abstract
Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), confer risk for Alzheimer’s disease (AD), a prospect substantiated by evidence of genetic association from several quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of β-amyloid (Aβ42) and the tau protein. In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent northern European case-control series encompassing 1323 individuals and including approximately 400 patients with measurements of CSF Aβ42 and phospho-tau protein levels. Tests of association in case-control models revealed limited evidence that CYP46A1 variants contributed to AD risk across these samples. However, models testing for potential effects upon CSF measures suggested a possible interaction of an intronic marker (rs754203) with age and APOE genotype. In stratified analyses, significant effects were evident that were restricted to elderly APOE ε4 carriers for both CSF Aβ42 (P=0.0009) and phospho-tau (P=0.046). Computational analyses indicate that the rs754203 marker probably does not impact the binding of regulatory factors, suggesting that other polymorphic sites underlie the observed associations. Our results provide an important independent replication of previous findings, supporting the existence of CYP46A1 sequence variants that contribute to variability in β-amyloid metabolism.
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Acknowledgements
Generous financial support was provided by Pfizer, the Loo and Hans Ostermans Foundation, the Knut and Alice Wallenberg Foundation, the National Institute on Aging (AG:08861), the Swedish Old Servants Foundation (Gamla Tjänarinnor), the Åke Wibergs Foundation, the Torsten and Ragnar Sàderbergs Foundation, the Fredrik and Ingrid Thurings Foundation, the Petrus and Augusta Hedlunds Foundation, and the Swedish Alzheimer Foundation (Alzheimerfonden).
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Johansson, A., Katzov, H., Zetterberg, H. et al. Variants of CYP46A1 may interact with age and APOE to influence CSF Aβ42 levels in Alzheimer’s disease. Hum Genet 114, 581–587 (2004). https://doi.org/10.1007/s00439-004-1107-9
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DOI: https://doi.org/10.1007/s00439-004-1107-9