Plasma 24S hydroxycholesterol response to statins in Alzheimer's disease patients: Effects of gender, CYP46, and ApoE polymorphisms

A number of epidemiologic studies suggest an association between plasma total cholesterol and risk for Alzheimer's disease (AD). Additionally, it has been suggested that treatment with statins, drugs that block cholesterol biosynthesis, lower the incidence and prevalence of AD and of vascular dementia. This review provides an overview of cholesterol transport within the central nervous system and the impact of statins on brain cholesterol metabolism in subjects with AD. Brain cholesterol is converted to 24-S-hydroxycholesterol, a reaction catalyzed by CYP46. The oxysterol traverses the blood-brain barrier and is transported to the liver by plasma lipoproteins. The levels of 24-S-hydroxy-cholesterol are a reflection of brain cholesterol turnover. Subjects with AD reportedly have high levels of the oxysterol possibly reflecting neuronal death with release of cell membrane cholesterol. We show gender dimorphism in plasma levels of 24-S-hydroxycholesterol in subjects with AD and significant reductions in plasma levels of the oxysterol during treatment with standard doses of statins (lovastatin, simvastatin, and pravastatin). Polymorphisms of apolipoprotein E and CYP46 do not influence the effect of statins on plasma levels of 24-S-hydroxycholesterol. There were no untoward effects of the standard doses of statin for the duration of treatment. Statins are currently in trial to determine their effect on the course of AD.