Tobias Hartmann led this live discussion on 19 November 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 28 August 2006

Background Text
By Tobias Hartmann

When it comes to therapeutic issues in Alzheimer's disease, there is one theme everyone in the field is talking about these days, and that is cholesterol. This is astounding considering that just two years ago the issue interested very few scientists and before that time it was hardly recognized at all. This is not because there were too few publications; more than 200 papers addressed this matter in one way or another (to name a few key ones, see [1-7]). But not all articles were of desirable quality, perhaps important methods were not broadly available, and it seems that, overall, the field doubted that cholesterol was truly relevant for AD.

The pace picked up when, in October 2000, Wolozin et al.[8] showed drastically decreased prevalence of AD in former statin users and an independent confirmation appeared the next month. [9]. In May 2001, our group presented an apparent explanation for this finding: statin-dependent Aβ42 reduction in neuronal cell cultures and, importantly, markedly reduced Aβ42 levels in a guinea pig model Fassbender et al.[10]. That June, Kivipelto et al.[12] identified high midlife cholesterol as AD risk factor and in October, Refolo et al.[11] confirmed our finding by using AD transgenic mice. In March of 2002, our group linked cholesterol transport to presenilin localization and APP processing [13] and this past September, less then a year after the first in vivo statin data appeared, Simons et al.[14] showed in a small, prospective pilot trial that simvastatin indeed reduce cerebral Aβ levels in AD patients. Several larger, prospective trials are now ongoing or are slated to start this year.

We owe this fast progress not only to the scientists involved but also to a remarkable amalgam of helpful circumstances. Statins are very widely used in heart disease. This obviates the need to go through painstaking work identifying and modeling new suitable molecules; statins can be picked right off the shelf. Moreover, they have a benign toxicity profile hardly matched by any other major pharmaceutical. Numerous large statin trials have convincingly shown a beneficial outcome even independent of elevated cholesterol levels[15]. Since there is no reason to believe that statins interact with acetylcholinesterase inhibitors, accepted treatments need not be interrupted. The door to large prospective clinical trials is wide open. Moreover, AD research can dig into a wealth of data generated during the last decades by arteriosclerosis research and related fields.

How does it work?
The approach is simple. Statins inhibit the activity of HMG-CoA reductase, an essential enzyme in the cholesterol biosynthetic pathway. Lowered neuronal cholesterol levels result in reduced β- and γ-secretase activity, possibly further enhanced by increased α-secretase activity. The net effect of statin treatment would be similar to a combined β- and γ-secretase inhibitor treatment, plus the anti-inflammatory side effects of statins may come in as a welcome freebie. However, this is a very young field in AD research. The fast scientific progress has left many essential questions unanswered, some of which may contradict and complicate this simple scheme.

I suggest we discuss the pressing, unresolved issues below:

• Vascular Dementia versus AD?
  The epidemiological data could be interpreted as a result of effects on vascular dementia. While the extent of overlap between vascular dementia and AD is a discussion topic by itself, there is general agreement that vascular dementia and AD often come together. Could it be that the positive outcome is due to a protective effect on vascular pathology and that the A benefit is just a welcome freebee? Moreover, high blood pressure also increases the risk for AD and vascular pathology[12]; does this indicate a vascular factor?

  Furthermore, inflammation has been a topic in AD research for some time. Statins have anti-inflammatory effects and this, too, may be related to vascular dementia. How important are the anti-inflammatory effects of statins? In-vitro and some in-vivo experiments show that the Aβ reduction by statins is dependent on cholesterol levels but independent of statin side effects. Even so, is this really the whole story?

• BBB?
  How can we explain that statins believed not to cross the blood-brain-barrier (pravastatin) are apparently protective? Some even think that statins that do cross the BBB are dangerous. Why-because they would lower brain cholesterol too much?

• Treatment or Prevention—Who Stands to Benefit the Most?
  High cholesterol levels during middle age appear to be an AD risk factor, but there is less agreement on cholesterol levels during clinical AD. If cholesterol does not participate in the disease process at this later disease stage, would statins be of use to AD patients or should they be used for prevention only? Is this issue the reason behind the finding in our pilot clinical study that patients might gain the most the earlier they are treated? Other treatment approaches, for example estrogen and NSAIDs, also wrestle with this issue of treatment versus prevention. How about sex differences? Bang from Suwon Korea reported in Orlando that only females, not males, of Tg2576 APP- transgenic mice reacted to high-dose lovastatin treatment with increased plaque formation. Male mice did not differ from controls at all.”

• ApoE?
  ApoE4 is the best-validated genetic risk factor we know. Its role has been explained by a difference in Aβ clearance, fibrillization, or apoE-dependent repair processes. But apoE shuffles cholesterol between cells, and apoE4 differs from apoE3 in this respect. The link appears to be obvious, but Kivipelto [16] just reported that the ApoE4 and middle-age cholesterol risk are unrelated. See news .

• Mechanism?
  Cholesterol levels affect secretase activity. But how this is done remains largely a mystery. Plenty of ideas are available, including an effect of cholesterol esters, but few hard facts are known. After all, why should the APP-degrading machinery be this sensitive to alterations in the lipid homeostasis? Furthermore, three different reports presented at the recent Society for Neuroscience meeting in Orlando indicate a role for ceramides and/or for gangliosides in Aβ production. It could be that the molecular mechanism actually works via one of these molecules rather than cholesterol. In this context, Luigi Puglielli in Dora Kovacs’ group suggested a second messenger- and senescence-related effect transmitted via ceramides rather than a direct lipid interaction effect.

• Where is the link to Aβ42
  When numerous diverse AD mechanisms were studied in detail, sooner or later a specific link to Aβ42 was identified. Take NSAIDs, for example. Until now, no such link had been found for cholesterol. Is this because there is none, or didn't we look in the right places yet?

References

1. Bodovitz, S. and W.L. Klein, Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J-Biol-Chem, 1996. 271(8): p. 4436-40. Abstract

2. Sparks, D.L., Intraneuronal β-amyloid immunoreactivity in the CNS. Neurobiol Aging, 1996. 17(2): p. 291-9. Abstract

3. Kalmijn, S., L.J. Launer, A. Ott, J.C. Witteman, A. Hofman, and M.M. Breteler, Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol, 1997. 42(5): p. 776-82. Abstract

4. Liu, Y., D.A. Peterson, and D. Schubert, Amyloid β peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci U S A, 1998. 95(22): p. 13266-71. Abstract

5. Simons, M., P. Keller, B. De Strooper, K. Beyreuther, C.G. Dotti, and K. Simons, Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A, 1998. 95(11): p. 6460-4. Abstract

6. Frears, E.R., D.J. Stephens, C.E. Walters, H. Davies, and B.M. Austen, The role of cholesterol in the biosynthesis of β-amyloid. Neuroreport, 1999. 10(8): p. 1699-705. Abstract

7. Refolo, L.M., M.A. Pappolla, B. Malester, J. LaFrancois, T. Bryant-Thomas, R. Wang, G.S. Tint, K. Sambamurti, and K. Duff, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis, 2000. 7(4): p. 321-31. Abstract

8. Wolozin, B., W. Kellman, P. Ruosseau, G.G. Celesia, and G. Siegel, Decreased prevalence of alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch Neurol, 2000. 57(10): p. 1439-43. Abstract

9. Jick, H., G.L. Zornberg, S.S. Jick, S. Seshadri, and D.A. Drachman, Statins and the risk of dementia. Lancet, 2000. 356(9242): p. 1627-31. Abstract

10. Fassbender, F., M. Simons, C. Bergmann, M. Stroick, D. Lütjohann, P. Keller, H. Runz, S. Kühl, T. Bertsch, K. von Bergmann, M. Hennerici, K. Beyreuther, and T. Hartmann, Simvastatin strongly reduces Alzheimer's disease Aβ42 and Aβ40 levels in vitro and in vivo. Proc Natl Acad Sci U S A, 2001. 98(10): p. 5856-61. Abstract

11. Refolo, L.M., M.A. Pappolla, J. LaFrancois, B. Malester, S.D. Schmidt, T. Thomas-Bryant, G.S. Tint, R. Wang, M. Mercken, S.S. Petanceska, and K.E. Duff, A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis, 2001. 8(5): p. 890-9. Abstract

12. Kivipelto, M., E.L. Helkala, M.P. Laakso, T. Hanninen, M. Hallikainen, K. Alhainen, H. Soininen, J. Tuomilehto, and A. Nissinen, Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. Bmj, 2001. 322(7300): p. 1447-51. Abstract

13. Runz, H., J. Rietdorf, I. Tomic, M. de Bernard, K. Beyreuther, R. Pepperkok, and T. Hartmann, Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci, 2002. 22(5): p. 1679-89. Abstract

14. Simons, M., F. Schwarzler, D. Lutjohann, K. von Bergmann, K. Beyreuther, J. Dichgans, H. Wormstall, T. Hartmann, and J.B. Schulz, Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol, 2002. 52(3): p. 346-50. Abstract

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

16. Kivipelto, M., E.L. Helkala, M.P. Laakso, T. Hanninen, M. Hallikainen, K. Alhainen, S. Iivonen, A. Mannermaa, J. Tuomilehto, A. Nissinen, and H. Soininen, Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med, 2002. 137(3): p. 149-55. Abstract

17. Puglielli, L., G. Konopka, E. Pack-Chung, L.A. Ingano, O. Berezovska, B.T. Hyman, T.Y. Chang, R.E. Tanzi, and D.M. Kovacs, Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol, 2001. 3(10): p. 905-12. Abstract

	Comments on Live Discussion
	Comment by:  Alexei R. Koudinov
	Submitted 14 November 2002  |  Permalink	Posted 14 November 2002
	Failure of neural cholesterol dynamics is a primary pathogenic event in sporadic Alzheimer's disease In my view, the "How does it work?" scheme and "Mechanism?" question posed by Tobias Hartmann should be enhanced with the perspective presented in our FASEB article (1) and in the hypothesis posted earlier this year on Alzforum (2, see also 3-5). In brief, we believe that the fundamental pathophysiological event in most common sporadic forms of Alzheimer's disease is a failure of accurate brain cholesterol homeostasis. It is advocated by the fact that neuronal cholesterol pathology proper is a sufficient event to cause major Alzheimer's features of synaptic and behavioral impairment, amyloid formation, excessive tau phosphorylation, neurite degeneration, neuronal cell death, cholinergic dysfunction and oxidative stress. Details and complete bibliography are available at (2). References: 1. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-1860 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje Available at: 2. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. AlzForum: Hypothesis page. Posted online 19 August 2002. Available at: 3. Simmonds MA. The emerging neurobiology of cholesterol. Neurobiology of Lipids Vol.1, 1 (2002) Published online August 30, 2002, 4. Wood WG et al. Cholesterol and Alzheimer's disease. Neurobiology of Lipids Vol.1, 4 (2002) Published online August 30, 2002, 5. Editorial material. 32nd Society for Neuroscience annual meeting neurobiology of lipids sessions. Neurobiology of Lipids Vol.1, 5 (2002) Published online September 23, 2002. View all comments by Alexei R. Koudinov
	Comment by:  Dora M. Kovacs, ARF Advisor
	Submitted 19 November 2002  |  Permalink	Posted 19 November 2002
	Although statins may well be a godsend for patients with cardiovascular disease and perhaps Alzheimer's disease, the cholesterol management market is currently looking beyond statins. Why? One hard fact is that time is getting close for the expiration of statin patents, and this is rapidly diverting the interest of pharmaceutical and biotechnology companies toward alternative classes of lipid-regulating products. In addition, two scientific points should be considered. First, while it is true that the toxicity profile of statins is relatively benign in patients with high cholesterol, the efficacy of these compounds is not absolute, achieving the desired lipid-lowering effects in 80-90 percent of patients. Thus, 10-20 percent of patients still require alternative products to effectively manage their cholesterol. Second, statins specifically lower LDL levels, but have only modest effects on other lipids. An effective therapy for patients with low HDL, atherosclerosis, or other lipid disorders would ideally consist of a combination of lipid-regulating products (which could...  Read more Although statins may well be a godsend for patients with cardiovascular disease and perhaps Alzheimer's disease, the cholesterol management market is currently looking beyond statins. Why? One hard fact is that time is getting close for the expiration of statin patents, and this is rapidly diverting the interest of pharmaceutical and biotechnology companies toward alternative classes of lipid-regulating products. In addition, two scientific points should be considered. First, while it is true that the toxicity profile of statins is relatively benign in patients with high cholesterol, the efficacy of these compounds is not absolute, achieving the desired lipid-lowering effects in 80-90 percent of patients. Thus, 10-20 percent of patients still require alternative products to effectively manage their cholesterol. Second, statins specifically lower LDL levels, but have only modest effects on other lipids. An effective therapy for patients with low HDL, atherosclerosis, or other lipid disorders would ideally consist of a combination of lipid-regulating products (which could include but would not be limited to statins). Alternative products for cholesterol management so far include extended-release niacin, cholesterol absorption inhibitors, acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. While statins are already being considered potential therapeutic agents for the treatment of AD, the safety of these drugs for elderly patients with normal cholesterol has not yet been determined. Although only 1 or 2 percent of patients with high cholesterol levels present with serious adverse effects to statin treatment, large clinical trials are only now being carried out in elderly patients with normal cholesterol levels to assess the safety of these compounds for the prevention and treatment of AD. While awaiting the outcome of these trials, especially concerning the efficacy of statins in lowering Aβ levels, it would be prudent at this juncture to already start considering alternative therapies for managing lipids in AD patients. ACAT inhibitors were shown to lower Aβ production in cells (see news). As two ACAT inhibitors are currently in clinical trials for the treatment of atherosclerosis, this study promises hope for non-statin lipid management in AD patients. Most likely, other non-statin strategies for lowering cholesterol and Aβ will also be emerging over the coming years. Thus, the likelihood is quite high that cholesterol-based therapies for treating or preventing AD will ultimately involve a series of drugs to choose from, guided by the specific lipid management requirements in each patient. View all comments by Dora M. Kovacs
	Comment by:  Glyn Wainwright
	Submitted 17 February 2011  |  Permalink	Posted 17 February 2011
	My associates were looking at cholesterol depletions and clinical effects of cholesterol loss from plasma membranes, and realized that the neuronal impact was huge. In a second review paper referenced below, we explored the implications of cholesterol depletion (as caused by glycation of ApoE in LDL) on membrane leakages and neuronal stress. References: Seneff S, et al. Nutrition and Alzheimer's disease: The detrimental role of a high carbohydrate diet. Eur J Intern Med (2011). View all comments by Glyn Wainwright

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