Alzheimer’s Disease & Dementia

Alzheimer’s disease (AD) is the most common cause of dementia with no cure at present. Cholesterol metabolism is closely associated with AD at several stages. While brain only accounts for 2-3% of the body weight, it occupies 25% of the total body cholesterol.Cholesterol ester (CE) is the storage form of cholesterol. In normal brains, CE levels are less than 1% of free, unesterified cholesterol. However, in the vulnerable regions of brain samples from late-onset AD patients, CE levels were 80% higher; in the brains of three AD mouse models, the CE levels rose to values 3 to 11 fold higher than those in control mice. In addition, when fed with a high-cholesterol diet, the brain CE content in human ApoE4 knock-in mice was 3-fold higher than that in human ApoE3 knock-in mice. These observations suggest a causal relationship between AD and increased CE content in the brain. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) converts free cholesterol to cholesteryl esters, and plays important roles in cellular cholesterol homeostasisin various tissues including the brain. Recent studies show that in a mouse model, blocking ACAT1 provides multiple beneficial effects on AD. Here I review the current evidence that implicates ACAT1 as a therapeutic target for AD. I also discuss the potential usage of various ACAT inhibitors currently available to treat AD.