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Trends Mol Med. 2003 Mar;9(3):94-101.

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

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McGill Centre for Studies in Aging, Douglas Hospital Research Centre, 6825 Lasalle Blvd, Verdun, Quebec, Canada H4H 1R3.


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.

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