There has been considerable excitement generated by findings that statins, which lower plasma cholesterol, may help protect against Alzheimer disease (see Wolozin et al., 2000, Jick et al., 2000, and also ARF related news story that questions the benefit of statins for AD). But is cholesterol really where the action is? After all, by inhibiting HMGCoA reductase, an essential enzyme in the synthesis of the lipid mevalonate, statins also prevent synthesis of isoprenoids. In fact, a recent paper from Sam Gandy’s group weighs in heavily on inhibition of isoprenoid production as the reason why statins may boost the presumably beneficial α-secretase cleavage of amyloid-β precursor protein (AβPP; see ARF related news story).

Now, in a paper in press in the Journal of Biological Chemistry, Robert Vassar and colleagues at Northwestern University, Chicago, also report that inhibition of isoprenoid synthesis has a major impact on AβPP cleavage. However, Vassar and colleagues found that blocking isoprenoid synthesis leads to accumulation of intracellular Aβ. The result suggests that the relationship among cholesterol, isoprenoids, and AβPP cleavage is far from simple and may be specific to cellular compartments.

To measure the effects of statins on AβPP cleavage, first author Sarah Cole and colleagues transfected liver cells (HEK-293 cells) with a construct that expresses human AβPP harboring the Swedish mutation found in certain familial cases of Alzheimer disease (AD). To distinguish between the effects of lowered isoprenoids and those of lowered cholesterol, Cole and colleagues used a combination of statin plus cholesterol (in the form of lipoproteins in fetal bovine serum) or statin plus a small amount of added mevalonate. The latter, they showed, was sufficient to drive synthesis of isoprenoids in the cells but insufficient to cause an increase in cellular cholesterol.

Under statin plus mevalonate (i.e., low cholesterol but normal isoprenoids), Cole and colleagues found that release of α-secretase-cleaved soluble fragments of AβPP (sAβPPα) into the cell medium went up, whereas release of soluble β-secretase fragments (sAβPPβ) and the Aβ peptide itself were reduced. Gandy and colleagues had reported similar findings, though they had attributed the effect to reduced activity of isoprenoid-modulated Rho/ROCK protein kinase activity. These kinases could contribute to ectodomain shedding of membrane proteins, the Gandy group argued (see ARF related news story). But what of blocking just isoprenoid production?

When the authors looked at the effects of statins plus exogenous cholesterol (i.e., low isoprenoids and normal cholesterol) they found an entirely different picture. This time, β-secretase activity and production of Aβ were both increased—inside the cell. The intracellular accumulation of Aβ is almost certainly linked to about a fourfold increase in full-length AβPP in these cells, suggesting that the lack of isoprenoids may lead to increased synthesis of AβPP, or the failure of its export to the cell membrane. In support of the latter hypothesis, the authors found that immature AβPP accumulated to a greater extent than the mature form, suggesting that the accumulation might be occurring in synthesis compartments, such as the endoplasmic reticulum. The authors found similar results when they tested statins in primary neuronal cultures.

Recent data has shown that mice that accumulate significant amounts of intraneuronal Aβ also have extensive neurodegeneration, suggesting that elevated intracellular Aβ could play a pathological role (see ARF related news story from last July’s conference in Philadelphia). As for whether statins could exacerbate such pathology if it existed in humans, Vassar, in the following Q&A, suggests that the drugs, which are held at bay by the blood-brain barrier, are unlikely to block isoprenoid synthesis in the CNS.—Tom Fagan.

Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of APP, beta-secretase cleaved fragments, and Abeta via an isoprenoid-dependent mechanism. J Biol Chem. 2005 Feb 17; [Epub ahead of print] Abstract

Q&A with Robert Vassar.

Q: What is the upshot of these findings?
A: The implications of our work are somewhat difficult to see because of the complexity of statin action and the distinct mechanisms of cholesterol and isoprenoids on Aβ cell biology. The important conclusions of our study are:
1. Low cellular cholesterol levels reduce Aβ secretion (as previously reported).
2. On the other hand, low cellular isoprenoid levels induce intracellular Aβ accumulation, as well as APP and β-cleaved fragments (this is a novel finding).
3. Cholesterol and isoprenoids have completely independent effects on Aβ secretion and accumulation, respectively (again, a novel finding).
4. We have identified two distinct pools of Aβ, an intracellular pool that is isoprenoid-dependent, and an extracellular pool that is cholesterol-dependent (a novel finding).
5. Similar results were obtained with primary neurons and astrocytes, as well as a neuroblastoma cell line.
6. The protective effects of statins are probably due to lower cerebral cholesterol levels (as previously suggested; but see below for an alternative hypothesis).
7. If intraneuronal Aβ accumulation is involved in AD pathogenesis, improving the function of the isoprenoid pathway may be beneficial for AD.

Q: Do your data imply that statin treatment might actually be harmful?
A: We don't believe so, because it is unlikely that statin concentrations get high enough in the brain to significantly inhibit isoprenoid synthesis and thus cause intraneuronal Aβ accumulation. Normal isoprenoid synthesis can still occur in cells even when mevalonate levels are too low to sustain adequate cholesterol synthesis (hence our ability to dissociate cholesterol effects from isoprenoid effects). Therefore, given the typically low statin doses that people take, cerebral cholesterol levels may be reduced while isoprenoid levels are normal, hence the protective statin effect. Alternatively, the protective statin effect may have nothing to do with cerebral cholesterol levels, but may instead be a secondary result of improved cardiovascular or cerebrovascular function. In my opinion, this hypothesis has not been adequately investigated, nor have experiments been performed that specifically test this possibility.

Q: Given that epidemiology has proposed statins to be protective, do your data imply that intraneuronal Aβ accumulation is irrelevant to the pathophysiology of AD?
A: No, our data do not imply that intraneuronal Aβ accumulation is irrelevant to AD. As in the answer to your second question, we believe that the protective statin effect may be due to either lower cerebral cholesterol levels or improved cardiovascular function, and that statins at clinical doses are unlikely to cause intraneuronal Aβ accumulation. The role of intraneuronal Aβ accumulation in AD is a completely separate issue and is still an open question. A number of different groups have observed intraneuronal Aβ accumulation in AD, Down's, and APP transgenic brains, so I have no doubt that it exists. However, its root cause is unknown and it is as yet unclear whether intraneuronal Aβ is toxic and is involved in the neurodegeneration that is observed in AD.

Regarding the implications of our work, we observed that low cellular isoprenoid levels induced intracellular Aβ accumulation. Therefore, we hypothesize that the intraneuronal Aβ accumulation observed in AD may result from isoprenoid deficiency in the neuron. If intraneuronal Aβ accumulation is toxic, then our work implies that increasing isoprenoid synthesis or function in neurons may prove to be an efficacious therapeutic strategy for the treatment of AD.

Q: Did mouse studies showing that statin treatment reduced amyloid deposition assess intraneuronal Aβ accumulation, or neuronal loss?
A: Good question. I don't know if anyone has looked carefully at this. My impression is that no one has investigated intraneuronal Aβ accumulation or neuronal loss in the statin-treated APP transgenics. Like human clinical doses, I don't think that the statin doses given to these mice were high enough to inhibit isoprenoid synthesis and cause intraneuronal Aβ accumulation, but they may have lowered cerebral cholesterol levels resulting in the decreased amyloid deposition.


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  1. 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.

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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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News Citations

  1. Philadelphia: All Is Not Well with the Statin Story
  2. Statins Boost α-Secretase, but Not Through Cholesterol
  3. Philadelphia: The Enemy Within—Neurodegeneration From Intraneuronal Aβ

Paper Citations

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

Further Reading


  1. . Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med. 2005 Jan;2(1):e18. PubMed.
  2. . 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. PubMed.


  1. Statins Reduce Brain Cholesterol Metabolite

Primary Papers

  1. . 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. PubMed.