Alzheimer's disease: the cholesterol connection

A hallmark of all forms of Alzheimer's disease (AD) is an abnormal accumulation of the beta-amyloid protein (AD) in specific brain regions. Both the generation and clearance of A-beta are regulated by cholesterol. Elevated cholesterol levels increase A-beta in cellular and most animals models of AD, and drugs that inhibit cholesterol synthesis lower A-beta in these models. Recent studies show that not only the total amount, but also the distribution of cholesterol within neurons, impacts A-beta biogenesis. The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD. Clinical trials have recently been initiated to test whether lowering plasma and/or neuronal cholesterol levels is a viable strategy for treating and preventing AD. In this review, we describe recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection.