Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease

There is much evidence suggesting that there is a strong relationship between the deterioration of brain lipid homeostasis, vascular changes and the pathogenesis of Alzheimer's disease (AD). These associations include: (1) recognition that a key cholesterol transporter, apolipoprotein E type 4, acts a major genetic risk factor for both familial and sporadic AD; (2) epidemiological studies linking cardiovascular risk factors, such as hypertension and high plasma cholesterol, to dementia; (3) the discovery that small strokes can precipitate clinical dementia in cognitively normal elderly subjects; (4) the modulation of degradation of the amyloid precursor protein by cholesterol administration in cell culture and in animal models of beta-amyloid overproduction; and (5) the beneficial effect of cholesterol-lowering drugs, such as Probucol and statins, in combating common AD. The recent finding that there is a genetic association between the HMGR gene locus and sporadic AD further suggests that brain cholesterol metabolism is central to AD pathophysiology, and a potential therapeutic target for disease stabilization and primary disease prevention.