Increased Brain β-Amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated With an Intronic CYP46 Polymorphism

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Abstract
THE CYP46 GENE encodes cholesterol 24-hydroxylase, the rate-limiting enzyme for cholesterol removal from the brain.1-3 Cholesterol 24-hydroxylase mediates the hydroxylation of brain cholesterol to 24-hydroxycholesterol that can be transported readily through the blood-brain barrier.4 Because depletion of brain cholesterol levels reduces the generation of β-amyloid peptides (Aβ),5,6 and because cholesterol-lowering drugs may reduce the risk of dementia,7,8 we tested whether polymorphisms of CYP46 are associated with brain β-amyloid load in humans by measuring the sequential pattern of β-amyloid deposition in the medial temporal lobe. Brain β-amyloid deposits contain large amounts of Aβ42. Consequently, we next tested whether CYP46 genotypes affected levels of Aβ42 in cerebrospinal fluid (CSF) obtained from patients with mild to moderate Alzheimer disease (AD).