The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into the periphery is probably an important step for the maintenance of brain cholesterol homeostasis. Recent findings suggest that plasma 24S-hydroxycholesterol may be elevated in Alzheimer's disease (AD) and vascular dementia at least at some stage of the disease, suggesting increased brain cholesterol turnover during neurodegeneration. We investigated whether plasma 24S-hydroxycholesterol concentrations depend on the severity of AD and on the apolipoprotein E (apoE) genotype. Severity of AD and inheritance of the apoE4 allele were independently associated with reduced plasma 24S-hydroxycholesterol/cholesterol ratios. The results suggest that the decrease of plasma 24S-hydroxycholesterol/cholesterol in severely affected AD patients is a peripheral marker for loss of cholesterol 24S-hydroxylase in the CNS. Inheritance of the apoE4 allele may be associated with increased apoE-mediated transport of brain cholesterol to the periphery or with decreased activity of the 24S-hydroxylase. Longitudinal studies will assess the validity of the ratio plasma 24S-hydroxycholesterol/cholesterol as a state marker for AD.
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