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.
Poirier
Judes
J
McGill Centre for Studies in Aging, Douglas Hospital Research Centre, 6825 Lasalle Blvd, Verdun, Quebec, Canada H4H 1R3. judes.poirier@mcgill.ca
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000150:complications; D002490:Central Nervous System / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D010743:Phospholipids / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010743:Phospholipids; D002784:Cholesterol; D008798:Mevalonic Acid