THIS ISSUE of the ARCHIVES presents an elegant study by Papassotiropoulos and colleagues,1 demonstrating that a polymorphism in the gene coding for Cyp46 (also known as 24S-cholesterol hydroxylase) is a major risk factor for late-onset Alzheimer disease (LOAD). The Cyp46 enzyme is a member of the cytochrome P450 family of proteins and converts cholesterol to 24-hydroxycholesterol (24-OHC).2 Cyp46 is expressed exclusively in the brain, where it regulates the elimination of excess cholesterol by adding a hydroxyl group to cholesterol, producing a product that is more soluble than cholesterol and able to be exported from the brain.2,3 Thus, cholesterol exits the brain by conversion to 24 OHC, and the amount of 24-OHC exiting the brain is thought to equal the amount of cholesterol endogenously synthesized within the brain. Less Cyp46 presumably leads to more brain cholesterol.
Wolozin B. Cyp46 (24S-Cholesterol Hydroxylase)A Genetic Risk Factor for Alzheimer Disease. Arch Neurol. 2003;60(1):16-18. doi:10.1001/archneur.60.1.16