CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism.
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).


CONCLUSIONS
Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.
Kölsch
Heike
H
Department of Psychiatry, University of Bonn, Germany. heike.koelsch@ukb.uni-bonn.de
Lütjohann
Dieter
D
Jessen
Frank
F
Popp
Julius
J
Hentschel
Frank
F
Kelemen
Peter
P
Schmitz
Sandra
S
Maier
Wolfgang
W
Heun
Reinhard
R
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006888:Hydroxycholesterols / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase