[Risk factors for Alzheimer's disease]

Apolipoprotein E (apoE) is the major risk factor, besides aging, for Alzheimer's disease (AD). Many hypotheses have been proposed to explain the mechanism whereby one of the isoforms of apoE, apoE4, could cause AD. We have been conducting studies on the pathogenic roles of apoE from the viewpoint of its physiological function. We previously reported that one detrimental effect of apoE4 on neuronal viability can be induced by alteration in intracellular cholesterol metabolism. In brains of patients with AD, there is a common pathological process, called the amyloid cascade. Therefore, one of the central questions regarding the pathogenic roles of apoE in the development of AD is how apoE4 enhances deposition of amyloid b-protein (A beta). In relation to this issue, evidence is now accumulating to show that the metabolism of amyloid precursor protein (APP) and A beta can be modulated by cellular cholesterol. Our recent studies revealed that a novel A beta with a unique ability to accelerate fibril formation of soluble A beta is generated in the presence of cellular cholesterol. These lines of evidence suggest that the alteration of cholesterol metabolism in neurons due to aging and/or expression of apoE4 may be a prerequisite for the development of AD.