Statins are one of the major “miracle” drugs developed by the pharmaceutical industry. They lower cholesterol (LDL) levels effectively, yet have few side effects [1,2]. They have additional appeal because they appear to exhibit beneficial actions toward other diseases such as osteoporosis, stroke, and inflammatory disorders. The reason for this appears to arise from the ability of statins to inhibit palmitoylation, which inhibits a variety of signal transduction pathways. Inhibition of signaling by rac and rho is particularly important because these pathways are thought to mediate inflammation. Statins also appear to modulate eNOS and neuroprotective proteins such as Bcl-2 [3-5].

The hypothesis that statins might be beneficial in therapy of Alzheimer disease is appealing because these medications have so few side effects. Whether statins are actually beneficial for treating AD remains in question, though. Many epidemiological studies suggested that statins might protect against AD, and these are supported by two small prospective clinical trials. But some large prospective...  Read more

Statins are one of the major “miracle” drugs developed by the pharmaceutical industry. They lower cholesterol (LDL) levels effectively, yet have few side effects [1,2]. They have additional appeal because they appear to exhibit beneficial actions toward other diseases such as osteoporosis, stroke, and inflammatory disorders. The reason for this appears to arise from the ability of statins to inhibit palmitoylation, which inhibits a variety of signal transduction pathways. Inhibition of signaling by rac and rho is particularly important because these pathways are thought to mediate inflammation. Statins also appear to modulate eNOS and neuroprotective proteins such as Bcl-2 [3-5].

The hypothesis that statins might be beneficial in therapy of Alzheimer disease is appealing because these medications have so few side effects. Whether statins are actually beneficial for treating AD remains in question, though. Many epidemiological studies suggested that statins might protect against AD, and these are supported by two small prospective clinical trials. But some large prospective clinical trials failed to observe a benefit associated with statins. Is this because statins don’t help in AD or are there other issues? One important question is whether all statins are equal. Newer statins, such as atorvastatin and rosuvastatin are more potent than the earlier statins, such as lovastatin. Simvastatin appears to be intermediate in potency, being sufficiently powerful to inhibit inflammation under some conditions, but not as potent as the newest statins [6,7]. The older statins, including lovastatin and simvastatin, are more lipophilic and penetrate the blood-brain barrier better than the newer hydrophilic statins such as atorvastatin or rosuvastatin, as well as pravastatin (which is actually “older”) [8,9]. This raises the possibility that lipophilic statins might exhibit actions that differ from those of hydrophilic statins. This could account for some of the confusion present in the clinical literature as it relates to dementia. Two large prospective trials examining whether simvastatin or atorvastatin might benefit patients with AD are ongoing, which should clarify this issue.

In the meantime, another debate in the field questions the mechanism of statins’ action in the brain. Multiple studies demonstrate that statins can lower Aβ secretion in cells, depending on the dose [10,11]. This presents the appealing hypothesis that statins might be able to delay the incidence or progression of AD by reducing Aβ production. However, most studies have failed to observe Aβ lowering in humans [12].

The current study by Riekse and colleagues addresses both the issue of comparative statin efficacy and putative mechanism of action. They compare the effects of pravastatin (which does not penetrate the BBB well) and simvastatin (which does penetrate the BBB) using an elegant prospective in vivo human trial examining CSF. Neither statin reduced Aβ, but simvastatin did reduce phospho-tau levels.

The interpretation of these data is nuanced. The absence of any change in Aβ levels suggests that statins don’t inhibit Aβ secretion in the brain. However, the dose of simvastatin (20 and 40 mg/day) was only moderate. Data from the cardiovascular literature indicate that one must use 80 mg/day of simvastatin to inhibit the HMG CoA reductase pathway sufficiently to reduce inflammation. However, the group did examine and observe a decrease in C-reactive protein, which suggests that the inflammatory pathway was inhibited. However, I think it is wise to interpret this study conservatively with respect to Aβ. The data are interesting because they show that simvastatin treatment induces a statistically significant reduction in phospho-tau. This suggests that simvastatin might be capable of exhibiting neuroprotective actions, which is consistent with data from Gibson Wood’s group showing that statins modulate growth factors and neuroprotective proteins [5]. The absence of any effect of pravastatin on phospho-tau highlights the potential importance of lipophilicity in statin action.

One final point to note is that the volunteers were all nondemented and many subjects were quite young (with the pravastatin group being younger than the simvastatin group). This means that the changes in phospho-tau were not necessarily related to the degenerative processes associated with AD.

The main impact of this study is that it highlights potential differences in action among the statins and illuminates possible actions of statins in the brain.

References:
1. Wolozin B, Brown J 3rd, Theisler C, Silberman S. 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. Review. Abstract

2. Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A. Re-assessing the relationship between cholesterol, statins and Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:63-70. Review. Abstract

3. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S. 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. Abstract

4. Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J. 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. Abstract

5. Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Muller WE, Wood WG. Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther. 2005 Feb;312(2):786-93. Epub 2004 Sep 9. Abstract

6. Hunninghake DB, Ballantyne CM, Maccubbin DL, Shah AK, Gumbiner B, Mitchel YB. Comparative effects of simvastatin and atorvastatin in hypercholesterolemic patients with characteristics of metabolic syndrome. Clin Ther. 2003 Jun;25(6):1670-86. Abstract

7. Karalis DG, Ross AM, Vacari RM, Zarren H, Scott R. Comparison of efficacy and safety of atorvastatin and simvastatin in patients with dyslipidemia with and without coronary heart disease. Am J Cardiol. 2002 Mar 15;89(6):667-71. Abstract

8. Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ. Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord. 2006;22(5-6):392-8. Epub 2006 Sep 7. Abstract

9. Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Pharm Res. 1994 Feb;11(2):305-11. Abstract

10. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. 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. Epub 2001 Apr 10. Abstract

11. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem. 2005 May 13;280(19):18755-70. Epub 2005 Feb 17. Abstract

12. Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. 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. Abstract

View all comments by Benjamin Wolozin

This study presents an intriguing preliminary finding supporting the involvement of lipophilic statins in AD tau pathophysiology. Statins are known to modulate enzymes involved in tau phosphorylation either directly or indirectly through inflammatory or Rho-mediated pathways, and the present results are consistent with this literature.

However, the authors’ assertion that the primary use of statins is in the delay of neurodegeneration rather than in the effective treatment of the disease may be premature, given that the definitive clinical trials designed to address this very question have yet to read out. Nevertheless, the paper adds to a growing body of literature supporting the pleiotropic effects of statins and potential benefit in AD beyond modulation of cholesterol-specific pathways.

View all comments by Holly D. Soares