title: Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis.
abstract: High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Ab) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD.Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Ab. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.
authors: Geriatric Research, Education and Clinical Center, VAMC, Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
authors: W Gibson
authors: WG
authors: Wood
authors: Ling
authors: L
authors: Li
authors: Walter E
authors: WE
authors: Müller
authors: Gunter P
authors: GP
authors: Eckert
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000009:adverse effects* / Q000096:biosynthesis / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000150:complications* / Q000188:drug therapy; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011817:Rabbits; D012717:Sesquiterpenes / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C044563:24-hydroxycholesterol; C004808:farnesyl pyrophosphate; D002784:Cholesterol; C002963:geranylgeranyl pyrophosphate
keywords: Alzheimer's disease; amyloid beta-protein; apolipoprotein E; cholesterol; isoprenoids; statins