Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in cholesterol and fatty acid synthesis. Recently, a polymorphism in the 5′-region of the SREBP-1a gene has been described to be correlated with alterations in the plasma levels of cholesterol. Consequently the relationship between this SREBP-1a gene polymorphism and Alzheimer’s disease (AD) alone and in combination with the apolipoprotein E (ApoE) 4 allele was evaluated. No association between SREBP-1a polymorphism alone and AD could be seen. However, in the group of healthy ApoE4 allele carriers, the number of homozygote SREBP-1a ΔG allele carriers was significantly higher than in AD patients. Cerebrospinal fluid levels of cholesterol were lower in AD patients who were carriers of the SREBP-1a ΔG allele, and the ratio of 24S-hydroxycholesterol to cholesterol was increased in these probands. Our data suggest a reduced risk of AD in carriers of an ApoE4 allele who are additionally homozygous for the SREBP-1a ΔG allele, which is possibly due to the influence of SREBP-1a polymorphism on brain cholesterol metabolism. This is the first report on a genetic factor which prevents the deleterious effect of the ApoE4 allele and thus reduces the risk of AD.

Keywords:
Sterol regulatory element-binding protein, Alzheimer’s disease, Apolipoprotein E4, Association, Interaction, Brain cholesterol, 24S-Hydroxycholesterol, Polymorphism, Cerebrospinal fluid, Brain
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© 2004 S. Karger AG, Basel
2004
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