Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis

• Published in: Journal of neurochemistry Vol. 129; no. 4; pp. 559 - 572
• Main Authors: Wood, W. Gibson, Li, Ling, Müller, Walter E., Eckert, Gunter P.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2014
• Subjects: Alzheimer Disease - etiology; Alzheimer Disease - prevention & control; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; amyloid beta‐protein; Animals; apolipoprotein E; Apolipoproteins E - metabolism; Astrocytes - metabolism; Brain; Cell Membrane - metabolism; Cells, Cultured; Cholesterol; Cholesterol - adverse effects; Cholesterol - biosynthesis; Cholesterol - blood; Cholesterol, Dietary - adverse effects; Disease Models, Animal; Humans; Hydroxycholesterols - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - complications; Hypercholesterolemia - drug therapy; isoprenoids; Mice; Models, Biological; Neurochemistry; Neurons - metabolism; Pathogenesis; Polyisoprenyl Phosphates - metabolism; Rabbits; Sesquiterpenes - metabolism; statins; apolipoprotein E; cholesterol; amyloid beta-protein; isoprenoids; Alzheimer's disease; statins
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12637

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 (Aβ) 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 Aβ. 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.
High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). This Review addresses the Pro's and Con's of whether cholesterol is a causative factor in AD, covering articles ranging from human to cell culture studies, both in vitro and in vivo. Among others, we review models of how abeta could act on a membrane and of how abeta might be perturbing cholesterol in a cell.
High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). This Review addresses the Pro's and Con's of whether cholesterol is a causative factor in AD, covering articles ranging from human to cell culture studies, both in vitro and in vivo. Among others, we review models of how abeta could act on a membrane and of how abeta might be perturbing cholesterol in a cell.