This paper is most remarkable. The authors show that statin treatment, which has long been thought to be beneficial for Alzheimer disease patients, has two independent and diverging effects on APP processing. In a novel in-vitro system, the authors have been able to decipher the cholesterol-dependent and isoprenoid-dependent role of statins. The effects are surprisingly different. While low cholesterol reduced APP processing and Aβ generation, as expected, low isoprenoid levels enhanced intracellular accumulation of APP and its proteolytic products, including Aβ. Several recent studies have implicated a potential role of intraneuronal Aβ as an early pathological hallmark in AD patients. Together with recent reports that intracellular accumulation of Aβ is observed prior to neuronal death in APP/PS1 mouse models, one wonders whether statin treatment is indeed beneficial for Alzheimer disease patients.

View all comments by Thomas Bayer

Have you considered the possibility that a mechanism of statin action in AD may be related to its stimulatory effect on cerebral blood flow?

View all comments by James Crawford

The paper by Cole and colleagues is a very elegant manuscript because it provides important new insights into how statins might affect APP processing. The observation that inhibition of isoprenoid metabolism increases intracellular Aβ accumulation is surprising and important for the field to realize. However, the enzymes that drive isoprenoid synthesis have a very high affinity for their substrates, which means that isoprenoid synthesis remains intact even when cholesterol synthesis is partially blocked. Whether statins would actually cause this [Aβ accumulation] to occur in vivo remains an open question because statin treatment does not necessarily fully reduce cholesterol synthesis under the conditions used clinically (depending on the particular statin and dose utilized). This manuscript is also important because it elegantly defines careful methods for dissecting out the effects of cholesterol metabolism on the cell. By defining four treatment paradigms, the authors provide a roadmap for future studies into cholesterol biology.

View all comments by Benjamin Wolozin

Downregulation of clathrin-mediated intracellular transport; desensitization of receptor-mediated ester endocytosis, and RNAi antisense against cell synthesis of cholesterol could prove a powerful synergy of therapeutic treatment in this area. Decreased hydrolytic activity in lysosmes would further ensure less risk of bursting a cell (although targeting specific lysis may prove useful in overly active glial that cannot be suppressed or reverted back to inactive state).

Isoprenoids that show a detrimental role to Alzheimers onset and progression might possibly show also show neuroprotective roles in future treatment modalities. Statins, although promising, are not the miracle some people belived they were.

View all comments by Jacob Mack

I find this paper encouraging to research in the area of statins and effects on various esters, their constituents and other biochmeical markers in Alzheimers. I am curious, though, how we may be able to maximize isoprenoid activity, lower cholesterol, (possibly through further clathrin downregulation), and block signal transduction cell receptors themselves. Maybe desensitize some and sensitize others in order to further find the efficacy of statins and new emerging delivery systems of them.

Would it be fair to say that optimum lysosomal activity coupled with repressed cell uptake of cholesterol; and combined with cannabinoid-mediated lipid interference (arachidonic acid and others) of endocytotoxicity might in fact deal with many of the extra- and intracellular amyloid deposits. Then by using CB-2 mediated immune response we would partially suppress microglial activation. Then follow that up with a regiment of antioxidants, for we know that amyloid and immune cells oxidize (either immune system dependent/coupled with) so much cortical/subcortical matter, and, of course...  Read more

I find this paper encouraging to research in the area of statins and effects on various esters, their constituents and other biochmeical markers in Alzheimers. I am curious, though, how we may be able to maximize isoprenoid activity, lower cholesterol, (possibly through further clathrin downregulation), and block signal transduction cell receptors themselves. Maybe desensitize some and sensitize others in order to further find the efficacy of statins and new emerging delivery systems of them.

Would it be fair to say that optimum lysosomal activity coupled with repressed cell uptake of cholesterol; and combined with cannabinoid-mediated lipid interference (arachidonic acid and others) of endocytotoxicity might in fact deal with many of the extra- and intracellular amyloid deposits. Then by using CB-2 mediated immune response we would partially suppress microglial activation. Then follow that up with a regiment of antioxidants, for we know that amyloid and immune cells oxidize (either immune system dependent/coupled with) so much cortical/subcortical matter, and, of course enzymes need their coenzymes. I read so much great research here at Alzforum, I would like to see more synergy among the various researchers.

View all comments by Jacob Mack

This excellent paper very elegantly untangled the differential and independent mechanisms by which Ab production is affected by isoprenoids and cholesterol. Unfortunately, the above discussion whether statin treatment in humans could increase intracellular Ab takes us away from the main and very important finding that the isoprenoid pathway is involved in Ab generation.

As it has been pointed out in the paper and in the Q&A section above, it is experimentally possible to use statins in vitro at a concentration that shuts off HMG-CoA reductase activity. Only under these specific circumstances the isoprenoid pathway is shut down too. For a number of reasons such an approach would be incompatible with life. Animals need cholesterol to maintain functional membranes, cells continuously shed cholesterol from the plasma membrane and this cholesterol must be replenished. Contrary to popular belief, cells produce most of their cholesterol needs themselves by de-novo synthesis, only a minor part is hepatocyte- or diet-derived.

Notwithstanding the perilous consequences of...  Read more

This excellent paper very elegantly untangled the differential and independent mechanisms by which Ab production is affected by isoprenoids and cholesterol. Unfortunately, the above discussion whether statin treatment in humans could increase intracellular Ab takes us away from the main and very important finding that the isoprenoid pathway is involved in Ab generation.

As it has been pointed out in the paper and in the Q&A section above, it is experimentally possible to use statins in vitro at a concentration that shuts off HMG-CoA reductase activity. Only under these specific circumstances the isoprenoid pathway is shut down too. For a number of reasons such an approach would be incompatible with life. Animals need cholesterol to maintain functional membranes, cells continuously shed cholesterol from the plasma membrane and this cholesterol must be replenished. Contrary to popular belief, cells produce most of their cholesterol needs themselves by de-novo synthesis, only a minor part is hepatocyte- or diet-derived.

Notwithstanding the perilous consequences of isoprenoid depletion, without HMG-CoA reductase activity the animal would sooner or later run out of cholesterol stores and die. Similar statin brain concentrations (0.25µM) as the minimal concentration used in the elegant in-vitro studies by Vassar had been reported in mice by Gibson Wood. These high levels were achieved by feeding 50 times the maximum clinical dose, could be maintained only for brief periods of time and steady state levels were considerably lower. Cell-culture studies define mechanisms, not therapeutic strategies. In light of the existing data, this part of the discussion is difficult to comprehend. The necessary statin dosage would have to be enormously above clinical standards before harmful accumulation of intracellular Ab occurs. That the patient would be dead by that time for other reasons shows only how unrealistic this discussion is. Like Robert Vassar, I don’t see any evidence that clinical statin dosages could possibly cause relevant intracellular Ab accumulation. In a way, millions of patients on statins give living confirmation for this year by year.

View all comments by Tobias Hartmann

The new paper raises legitimate questions regarding the potential for artifactual associations emerging from epidemiological studies. My position remains cautiously optimistic because of the faint but positive signal emerging from the Sparks et al. trial (see ARF related news story). Randomized, double-blind placebo-controlled clinical trial data trump epidemiological data every time. The size of the Sparks et al. study (<50 subjects) tempers my enthusiasm, and, like others, I await the results of the large simvastatin clinical trial that is headed by Mary Sano and the ADCS.

View all comments by Samuel Gandy

The cholesterol and statin story in AD has been a never-ending battle since its inception in the late 1980s, and the current paper sends a mixed message. It seems that if the authors exclude the final year of medications from consideration, there is no reduced hazard risk (HR), but if the final year of current statin use is included in the analysis, there is a near significant or significant (for AD with or without vascular factors) reduction in the hazard ratio. One must also consider that an individual who may have taken a statin for, say, 1 month would be included in the "ever statin use." I would suggest the take-home message may be that longer exposure to statins produces a reduced risk of AD later in life.

I am sure that the statin story with regard to treatment of AD will be sorted out by the results of LEADe and CLASP: the two large multicenter trials testing atorvastatin and simvastatin, respectively. The way to determine the effect of statins on prevention of AD (reduced risk) is to directly test for benefit in a double-blind, placebo-controlled prevention trial of...  Read more

The cholesterol and statin story in AD has been a never-ending battle since its inception in the late 1980s, and the current paper sends a mixed message. It seems that if the authors exclude the final year of medications from consideration, there is no reduced hazard risk (HR), but if the final year of current statin use is included in the analysis, there is a near significant or significant (for AD with or without vascular factors) reduction in the hazard ratio. One must also consider that an individual who may have taken a statin for, say, 1 month would be included in the "ever statin use." I would suggest the take-home message may be that longer exposure to statins produces a reduced risk of AD later in life.

I am sure that the statin story with regard to treatment of AD will be sorted out by the results of LEADe and CLASP: the two large multicenter trials testing atorvastatin and simvastatin, respectively. The way to determine the effect of statins on prevention of AD (reduced risk) is to directly test for benefit in a double-blind, placebo-controlled prevention trial of 6-10 years' duration. In advance of expending the time and monies to perform such a prevention trial, I would suggest identifying benefit of statin therapy in delaying the transition from MCI to AD in a double-blind, randomized placebo-controlled MCI treatment trial would strongly support possible success in a prevention trial.

View all comments by Larry Sparks

The recent epidemiological study by Rea and colleagues adds yet more complexity (and confusion) to the issue of statin use and AD risk. It’s difficult to draw any firm conclusions from the study, since the reported outcomes vary so distinctly as a function of analysis parameters. The gold standard will always be double-blind, case-controlled studies, and for good reason. The results from the statin clinical trial(s) in the pipeline will hopefully shed more light on this important issue.

The Rea study does, however, bring to light a couple of general issues (some of which have been discussed previously on Alzforum) that may or may not be resolved in the upcoming prospective clinical trials (e.g., CLASP). If statin use indeed influences AD risk, what duration of use is needed to achieve the effect? I don’t think the “ever use” versus “never use” in the Rea paper is useful in sorting this out. And perhaps more importantly, when do statins need to be taken in order to achieve proposed protection? AD pathology is known to begin years, perhaps decades, prior to cognitive symptoms....  Read more

The recent epidemiological study by Rea and colleagues adds yet more complexity (and confusion) to the issue of statin use and AD risk. It’s difficult to draw any firm conclusions from the study, since the reported outcomes vary so distinctly as a function of analysis parameters. The gold standard will always be double-blind, case-controlled studies, and for good reason. The results from the statin clinical trial(s) in the pipeline will hopefully shed more light on this important issue.

The Rea study does, however, bring to light a couple of general issues (some of which have been discussed previously on Alzforum) that may or may not be resolved in the upcoming prospective clinical trials (e.g., CLASP). If statin use indeed influences AD risk, what duration of use is needed to achieve the effect? I don’t think the “ever use” versus “never use” in the Rea paper is useful in sorting this out. And perhaps more importantly, when do statins need to be taken in order to achieve proposed protection? AD pathology is known to begin years, perhaps decades, prior to cognitive symptoms. Is it mid-life use that protects against future late-life dementia, or will late-life statin use also be of some benefit? By enrolling only demented patients (mild and moderate), the CLASP study will be able to address the issue of efficacy of statin use in preventing clinical progression, but what about preventing or slowing pathologic progression prior to symptoms? This is a much more difficult question to answer and even test. I think it’s still unclear from the human literature whether statins are able to influence the disease process itself or if they merely influence the symptoms. While we’ll take any protective effect we can get, finding an AD treatment that would stop or even slow disease progression at its earliest stages (especially preclinically) is clearly the ultimate goal.

View all comments by Anne Fagan

Recently there has been much debate as to whether statin therapy offers a benefit for Alzheimer disease (AD), and whether statins reduce AD incidence and/or progression remains an open question (Jick et al., 2000; Wolozin et al., 2000; Shepherd et al., 2002; Zandi et al., 2005; Sparks et al., 2005). The prospective cohort study by Rea and colleagues is certainly interesting, and several important factors are brought into consideration, including analysis of the effects of statin use duration, the type of statin used (lipophilicity profile) and patient characteristics. Most importantly, however, this study demonstrates how analysis of the same data set in two different ways can lead to diverging conclusions. Their analysis indicates that antecedent statin use in the population of elderly patients examined was not associated with a lower risk of dementia when primary analysis incorporated a 1-year lag. However, if the data is analyzed in a way similar to that of case-controlled studies, whereby analysis was based on current statin use compared to non-use, without a lag period,...  Read more

Recently there has been much debate as to whether statin therapy offers a benefit for Alzheimer disease (AD), and whether statins reduce AD incidence and/or progression remains an open question (Jick et al., 2000; Wolozin et al., 2000; Shepherd et al., 2002; Zandi et al., 2005; Sparks et al., 2005). The prospective cohort study by Rea and colleagues is certainly interesting, and several important factors are brought into consideration, including analysis of the effects of statin use duration, the type of statin used (lipophilicity profile) and patient characteristics. Most importantly, however, this study demonstrates how analysis of the same data set in two different ways can lead to diverging conclusions. Their analysis indicates that antecedent statin use in the population of elderly patients examined was not associated with a lower risk of dementia when primary analysis incorporated a 1-year lag. However, if the data is analyzed in a way similar to that of case-controlled studies, whereby analysis was based on current statin use compared to non-use, without a lag period, statin use appears somewhat beneficial in protecting against dementia. Thus, this study not only indicates that different results are obtained when a lag period is incorporated into the study design, but also ultimately questions whether statins affect the development of dementia at all.

However, it should be considered that AD is a slow and insidious disease, with abnormal physiological alterations likely preceding the clinical manifestations of the disease by several decades. Indeed, familial AD (FAD) mutations are known to elevate the levels of Aβ42 and thus, while patients with FAD likely overproduce Aβ42 from an early age, clinical symptoms are not typically observed until the third to fifth decades. In the current study, participants had a mean age of 75 years and, as discussed, it may well be the case that statin exposure much earlier in life may be required in order for these drugs to beneficially affect dementia risk. In addition to examining a younger population, it may also be of benefit to extend the lag period; given the insidious nature of AD, a year may not be sufficient for statins to beneficially affect the underlying pathophysiology.

In summary, while there is no doubt that this study provides important insights for the analysis of cohort studies, future prospective studies involving the analysis of a younger population and incorporating longer lag times in the study design would be informative. Ultimately, to provide the definitive answer to the question, are statins protective in AD?, it may be necessary to perform primary prevention studies to determine whether continuous long-term statin use in mid-life (long before the onset of dementia) could prevent or significantly delay AD.

View all comments by Sarah L. Cole
View all comments by Robert Vassar

We would like to respond to Dr. Wolozin on his disagreement with the interpretations of our results. His views focus mainly on cholesterol synthesis, when, in fact, our work suggests that changes in cholesterol synthesis are not responsible for the “cholesterol sequestration” phenotype observed in neurons challenged with Aβ during the experimental window. Although the finding that Aβ inhibited cholesterol synthesis seemed paradoxical to the intensive filipin staining, it is not unprecedented since the drug U18666A is a potent inhibitor of cholesterol synthesis and induces a similar pattern of cholesterol sequestration. Our rationale for examining SREBP-2 as the target for Aβ came from the observations that, although both Aβ and pravastatin significantly reduced cholesterol synthesis, pravastatin (at the concentration used in our study) did not cause cholesterol sequestration, nor did it cause apoptosis.

Moreover, in agreement with Dr. Wolozin’s concepts on HMGCoA and prenylation, we did not observe any significant change in protein prenylation in neurons treated with...  Read more

We would like to respond to Dr. Wolozin on his disagreement with the interpretations of our results. His views focus mainly on cholesterol synthesis, when, in fact, our work suggests that changes in cholesterol synthesis are not responsible for the “cholesterol sequestration” phenotype observed in neurons challenged with Aβ during the experimental window. Although the finding that Aβ inhibited cholesterol synthesis seemed paradoxical to the intensive filipin staining, it is not unprecedented since the drug U18666A is a potent inhibitor of cholesterol synthesis and induces a similar pattern of cholesterol sequestration. Our rationale for examining SREBP-2 as the target for Aβ came from the observations that, although both Aβ and pravastatin significantly reduced cholesterol synthesis, pravastatin (at the concentration used in our study) did not cause cholesterol sequestration, nor did it cause apoptosis.

Moreover, in agreement with Dr. Wolozin’s concepts on HMGCoA and prenylation, we did not observe any significant change in protein prenylation in neurons treated with pravastatin. This suggests that the conditions of pravastatin treatment were insufficient to achieve enough HMGCoA inhibition, even though we did not measure HMGCoA reductase activity or levels. At no point in our work have we claimed that HMGCoA reductase was involved in the effects of Aβ, and we would not be confident to directly extrapolate levels of HMGCoA reductase from SREBP-2 levels; thus, we do not understand the remark about accuracy that has been made. Finally, as Dr. Wolozin suspected, SREBP-2 regulates many other enzymes of the mevalonate pathway including farnesyl diphosphate synthase, which catalyzes formation of farnesyl-PP; therefore, inhibition of SREBP-2 can be expected to have a higher impact on prenylation. We believe that our work presents strong evidence that SREBP-2 is a target of Aβ. We have identified one pathway affected by the decrease of nuclear SREBP-2, but we expect that other targets of SREBP-2 could also play important roles.

References:
Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32. Abstract

Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002 May;109(9):1125-31. Abstract

View all comments by Amany Mohamed
View all comments by Elena Posse de Chaves