[A version of this item appears in: Dementia: the Latest Evidence Newsletter (RWHT), Volume 2 Issue 5, December 2011].
A two-part systematic review looks into the evidence for high cholesterol levels having an influence on the development of Alzheimer’s Disease (AD) and for the use of lipid-lowering agents (statins) as potential preventive or therapeutic medications.
Part 1: Review of Epidemiological and Preclinical Studies
This part of the review discusses the large body of evidence supporting the hypothesis that raised cholesterol levels increase the risk of developing Alzheimer’s Disease (AD). Epidemiological research on cholesterol level and the risk of AD is reviewed. The evidence appears to be inconsistent, in that some studies find beneficial effects, but others do not.
The molecular mechanisms likely to be behind any adverse effects of cholesterol on the development of AD are then discussed. Pre-clinical studies of statin use are shown to provide a basis and rationale for proposing statins as potential therapeutic agents.
Full Text Link (a) (Access online requires a journal subscription or a suitable Athens password).
Shepardson, NE. Shankar, GM. [and] Selkoe, DJ. (2011). Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Archives of Neurology, October 2011, Vol.68(10), pp.1239-44. (Click here to view the PubMed abstract).
Part 2: Review of Human Trials and Recommendations
Human trials of statins for preventive or therapeutic use are reviewed. The authors point to highly variable outcomes, and the inability to draw firm conclusions.
Various confounding factors in human studies are suggested as causes for the variability in the evidence, such as differing blood-brain barrier permeability across statins, the stage in Alzheimer’s Disease at which the statins are administered, and the “pleiotropic” metabolic effect of statins (i.e. their being potentially responsible for – or affecting – more than one phenotypic characteristic). Statins have effects on physiology and metabolism other than lowering cholesterol levels, and these could alter the risk of Alzheimer’s Disease independently. Statins may, for example, alter the expression of genes related to cell growth, signaling, trafficking and apoptosis.
The authors recommend that future human research takes into account the blood-brain barrier permeabilities of statins, the differences between low-density and high-density lipoprotein cholesterol, and advise on the need to concentrate statin treatment trials on patients with mild Alzheimer’s Disease (i.e. the sub-population with more scope for demonstrating unambiguous disease modification).
Full Text Link (b) (Access online requires a journal subscription or a suitable Athens password).
Shepardson, NE. Shankar, GM. [and] Selkoe, DJ. (2011). Cholesterol Level and Statin Use in Alzheimer Disease: II. Review of Human Trials and Recommendations. Archives of Neurology, November 2011, Vol.68(11), pp.1385-92. (Click here to view the PubMed abstract).