There is increasing evidence based on genetics, epidemiology, and more recently, cell biology that implicates cholesterol in the pathogenesis of AD.55,56 The principal cholesterol-carrier protein in the brain is Apolipoprotein E (ApoE), and the Apos4 allele is the only confirmed genetic risk factor for late-onset AD. ApoE and ApoJ (also called clusterin), two abundantly expressed apolipoproteins in the brain, both act as Afi chaperones and cooperatively suppress Afi levels and deposition in the brain.57 In addition to its role as a chaperone, ApoE also regulates the metabolism of Afi in the brain extracellular space.57 There are increasing genetic data (see the next section) that implicate several other genes in the cholesterol pathway, such as cholesterol 24-hydroxylase, in AD. In the cell, cholesterol impacts membrane structure, and APP, BACE1, and all four components of the y-secretase complex (presenilin 1, nicastrin, APH-1, and PEN-2) are membrane-associated proteins. Reducing cholesterol esters by inhibiting acyl-coenzyme A cholesterol acyltransferase (ACAT) reduces Afi secretion.58 Accumulation of intracellular cholesterol is accompanied by accumulation of presenilin 1 in the endosomal pathway and increased Afi production.59 Despite significant correlative data, the molecular mechanism of how cholesterol affects Afi levels is not yet fully understood. The epidemiological evidence comes from the observations that the incidence of AD is reduced by almost 70% among statin users.56,60 Definitive clinical efficacy trials are currently underway with several statins, such as simvastatin (phase 3) and atorvastatin (phase 2).
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