. Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol. 2004 Mar;61(3):333-7. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. The paper suggests that statin treatment (simvastatain and atorvastatin) has no major effect on plasma Aβ levels, as detected by ELISA. What does this mean? First, it is not clear that plasma Aβ levels are a useful index of AD pathology. CSF Aβ levels could have been a more interesting outcome, but these tend to drop with progression of the disease state, perhaps reflecting formation of insoluble aggregates, so it's not clear what outcomes one should expect with an effective AD treatment. It is interesting that both a hydrophobic statin (simvastatin) and hydrophilic drug (atorvastatin) gave similar effects in this experiment—but, since the results were essentially negative, it is again not clear how we should interpret this finding.

    The "statin story" in AD is still alive, but it's certainly confusing at present. More data are coming, so stay tuned.

  2. This interesting article by Hoglund and colleagues shows that statins do not lower plasma Aβ levels in patients treated with statins. The work is well-designed and well-controlled. The investigators studied two different statins, simvastatin and atorvastatin, which have different blood-brain barrier permeabilities, yet had similar results. Statins have been shown to modulate the levels of a number of plasma proteins that also bind Aβ, such as the apolipoproteins, which raises the possibility that the apparent absence of Aβ modulation by statin was due to competition for the ELISA with other blood-based proteins, or sequestration of free Aβ by binding to plasma proteins (Hernandez-Perera et al., 1998; Hernandez-Perera et al., 2000; Martin et al., 2001). However, the authors examined Aβ levels by immunoblotting, which is less sensitive to such artifacts related to competition for antibody binding, but this method also failed to show any changes in Aβ levels due to statin treatment. The strength of the design of the study means that the conclusions demand attention. The work adds to a recent manuscript showing that statins do not lower Aβ levels in CSF (Fassbender et al., 2002), but contradicts a prior report showing that lovastatin does lower plasma Aβ levels (Friedhoff et al., 2001).

    The potential inability of statins to lower Aβ in humans is surprising, given recent research. Statins have been shown to lower the brain-specific cholesterol catabolite 24-hydroxycholesterol in humans, which means that the statins are able to modulate cerebral cholesterol metabolism (Vega et al., 2003). In addition, statins have been shown to lower brain and plasma Aβ in guinea pigs, and to reduce amyloid plaque load in mice (Fassbender et al., 2001; Petanceska et al., 2002). This body of research has led many investigators, including myself, to advocate the hypothesis that statins provide a potential therapeutic approach to lowering Aβ and delaying the onset or progression of AD in humans. If the current results hold up, the data suggest a potential difference between the responsiveness of cerebral Aβ to statins between humans and lower animals (guinea pigs and mice). This is clearly an important question to be addressed.

    The significance of this manuscript lies in the relevance to therapy of Alzheimer’s disease (AD). Several epidemiological studies show lower prevalence or incidence of Alzheimer’s disease in subjects who take statins (Jick et al., 2000; Wolozin et al., 2000; Rockwood et al., 2002; Yaffe et al., 2002). Prospective trials have produced mixed results, with one small study suggesting that statins protect against AD, two large studies not (Group, 2002; Shepherd et al., 2002). In addition, results from a much-anticipated study of atorvastatin by Larry Sparks are expected in the next two months. These data suggest that statins affect the pathophysiology of AD, but further studies need to be performed to gain perspective on the degree of benefit that statins might provide, and whether statins are valuable as a preventive measure for AD or as a measure that is more useful in subjects who already have clinical symptoms.

    I would hesitate to conclude at this point that statins don’t impact APP processing in humans. However, it is interesting to speculate on mechanisms unrelated to Aβ metabolism by which statins might impact on the pathophysiology of AD. The term pleiotropic is often brought up when discussing the actions of statins. The cholesterol biosynthetic and catabolic pathways contribute to many biochemical functions, such as activation of small GTPases, bile acid metabolism, oxysterol metabolism, steroid production, and other functions (Wolozin et al., 2004). One of the most significant direct effects of statins that are not directly related to cholesterol reduction is the inhibition of protein prenylation. Proteins such as Rho, Ras and Rac are all prenylated by the actions of either geranylgeranyl transferase or farnesyl transferase (Zhang and Casey, 1996). Statins inhibit the actions of these two transferases by reducing the levels of the substrates (geranylgeranyl pyrophosphate and farnesyl pyrophosphate), which are generated from the same biochemical pathway that generates cholesterol (Wolozin, 2004b) (Guijarro et al., 1998). Inhibition of prenylation inhibits the actions of the small GTPases, Rho, Ras and Rac, which leads to a number of potentially important physiological effects. By inhibiting prenylation, statins inhibit ApoE secretion and iNOS production (Hernandez-Perera et al., 1998; Hernandez-Perera et al., 2000; Naidu et al., 2002). In addition, statins also appear to directly affect T cell action (Youssef et al., 2002). ApoE is thought to increase Aβ aggregation, and inflammation is thought to promote neurodegeneration induced by Aβ. Rho, Ras and Rac are involved in a myriad of biological processes, which raises the possibility that statins might also act on other physiological pathways relevant to AD. For instance, statins also increase secretion of both VEGF and ApoA1 (Martin et al., 2001; Maeda et al., 2003). If future studies continue to demonstrate that statins do not alter Aβ levels, and if future studies provide further evidence that statins are beneficial to patients with AD, then it would be wise to consider alternative mechanisms by which statins might impact on the pathophysiology of AD.

    References:

    . Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology. 2002 Oct 22;59(8):1257-8. PubMed.

    . Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. PubMed.

    . Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol. 2001 Jun;4(2):127-30. PubMed.

    MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22. PubMed.

    . 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res. 1998 Sep 7;83(5):490-500. PubMed.

    . Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res. 2000 Sep 29;87(7):616-22. PubMed.

    . Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998 Jun 15;101(12):2711-9. PubMed.

    . Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. PubMed.

    . Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology. 2003 Feb;144(2):681-92. PubMed.

    . Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest. 2001 Jun;107(11):1423-32. PubMed.

    . Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins. Brain Res. 2002 Dec 20;958(1):100-11. PubMed.

    . Statin therapy for Alzheimer's disease: will it work?. J Mol Neurosci. 2002 Aug-Oct;19(1-2):155-61. PubMed.

    . Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002 Feb;59(2):223-7. PubMed.

    . Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. PubMed.

    . Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease. Arch Neurol. 2003 Apr;60(4):510-5. PubMed.

    . The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer's disease. CNS Drug Rev. 2004 Summer;10(2):127-46. PubMed.

    . Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. PubMed.

    . Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol. 2002 Mar;59(3):378-84. PubMed.

    . The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002 Nov 7;420(6911):78-84. PubMed.

    . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241-69. PubMed.