Statins have recently appeared on the radar screen for Alzheimer's researchers because of studies by Ben Wolozin and his colleagues showing that people who take the cholesterol-lowering drugs have a significantly reduced risk of Alzheimer's disease (see Wolozin, et al., Arch Neurol. 2000). The drugs reduce cholesterol levels by inhibiting the activity of a liver enzyme called 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and Konrad Beyreuther has proposed that reductions in cholesterol can alter APP metabolism so as to reduce production of A-β. New findings suggest that statins have other potent biologic effects, which might also account for the reported reduction in AD risk. A team led by François Mach at University Hospital Geneva reports in the December issue of Nature Medicine that statins block the ability of a cytokine called interferon-γ (IFNγ) to activate T cells. Normally, IFN-γ causes T cells to express the major histocompatibility complex class II (MHC-II) molecule that takes in foreign antigens and presents them on the surface of immune cells, thus propagating the inflammatory response. Comments Wolozin: "Our research suggests that statins might reduce the risk of Alzheimer's disease by a mechanism independent of the effects of statins on serum cholesterol. The actions of statins on the immune system could contribute to the protective effects of statins for AD, given the potential importance of inflammation in the pathophysiology of Alzheimer's disease. In addition, this work emphasizes that many of the beneficial effects of statins, such as the ability to reduce the risk of AD, could be independent of serum cholesterol."—June Kinoshita

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  1. [I would like to note] that back in [August] 2000, we published a paper in Neurobiology of Disease (Refolo et al., 2000) demonstrating for the first time that cholesterol metabolism accelerates β-amyloid accumulation in a transgenic mouse model of AD. We show that diet-induced hypercholesterolemia alters APP processing in a manner giving rise to more A-β. What Beyreuther did was in cell lines. Our work used one of the best animals models for AD available.

    References:

    . Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. PubMed.

  2. This paper is most significant because it establishes that cholesterol plays a regulatory role in vivo in the pathogenesis of the AD lesions.

    View all comments by Marcia Simovich

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Primary Papers

  1. . Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. PubMed.
  2. . Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. PubMed.