Thought the shades were drawn on statins and Alzheimer’s disease? Not so. A December 12 JAMA Neurology report reopens the curtains just a crack with a large observational study on a diverse cohort of almost 400,000 Medicare beneficiaries who were prescribed statins to lower their cholesterol. Scientists led by Julie Zissimopoulos, Robert Diaz Brinton, and Geoffrey Joyce, University of Southern California, Los Angeles, found that cognitively normal people who took these drugs regularly over a three-year period were 10 percent less likely to develop Alzheimer’s than those who took them only part of that time. While the risk differed slightly depending on a person’s race, gender, and type of statin, a drop occurred almost across the board. The results revive the debate about whether statin use is associated with a lower incidence of AD.

“This goes a long way toward answering a nagging question,” said Ben Wolozin, Boston University, who was not involved in the research. “Statins have been shown in mixed and male populations to be associated with protection, but are they effective in women and the major nonwhite populations? The answer there is yes.” It’s yet another example of statins working to prevent AD when used for a prolonged period before cognitive impairment, Wolozin said. However, he believes the results don’t necessarily justify another clinical trial.

Previous epidemiological studies by Wolozin and others have hinted that statins reduce the risk of Alzheimer’s disease (Jick et al., 2000; Jul 2007 news). Other studies reported a neutral or even negative relationship (e.g., Zandi et al., 2005), and the question remained unsettled (see AlzRisk assessment of statin literature).

The prospect that an approved, inexpensive, widely available class of drugs might head off AD created intense excitement in the field for some years. Alas, as was the case with other potential treatment approaches that emerged from epidemiological observations, subsequent clinical trials failed to find a protective effect (e.g. Feldman et al., 2010Sano et al., 2011). 

These trials tended to enroll white men, have limited follow-up, and exclude people with hyperlipidemia—those who stand to benefit the most from taking these drugs, said Zissimopoulos. Many trials also compared users to nonusers. A more apt comparison would come from matching high to low users, as being prescribed these medications in the first place would indicate a more similar cardiovascular risk profile, she said. Zissimopoulos and colleagues realized they could use Medicare data to make these comparisons and follow people for years after exposure.

They chose the time period from 2006 to 2013 to examine nearly 400,000 Medicare beneficiaries aged 65 and older. Included among them were 310,240 white, 32,658 Hispanic, and 32,278 black people. Another 24,803 were of Asian, Native American, or unknown ancestry. Everyone was cognitively normal during the first three years of the study. During that time, the researchers noted which medicines were prescribed and how often people filled those prescriptions. They then checked who was diagnosed with AD over the next five years. The group was divided according to how often they took a statin: High users frequently filled their prescriptions for two years straight. Low users took their meds only part of the time.

Between 2009 and 2013, 1.72 percent of women and 1.32 percent of men were diagnosed with Alzheimer’s annually. Overall, high statin users had a 10 percent reduced chance of developing AD than low users. Both groups together had an average 20 percent lower chance of being diagnosed when compared to an additional 405,000 people who used no statins at all.

Analyzing the data by gender, race, and statin type suggested that risk depended somewhat on each of these factors. For example, simvastatin, the most commonly prescribed drug, lowered risk for all whites, Hispanics, and for black women. Atorvastatin lowered risk for white and black women as well as Hispanics. Pravastatin and rosuvastatin only worked to reduce risk in white women. Though there was a trend toward lowered risk, no statin reached statistical significance in black men. Zissimopoulos noted that black men comprised the smallest subsample of the study. With more samples, they might have seen an effect, she said.

“We are finding that statins are associated with reducing the risk of AD, and this is fairly robust,” said Zissimopoulos. She cautioned that only a clinical trial can prove causation. If a future trial included people with hyperlipidemia, followed them for several years, and analyzed people of diverse races and ethnicities, the trial could turn out differently than the negative trials so far, she believes. She is currently examining how statins combined with other drugs affect the risk of Alzheimer’s.

Other scientists took a more reserved stance. “This paper may help clarify at least some of the conflicting literature about the statin-AD relationship and, in particular, the failure of several trials to show a significant benefit of these drugs,” wrote John Breitner, McGill University, Montreal, to Alzforum. “But with an effect size so small, [a clinical trial] would require huge numbers of enrollees and cost tens of millions of dollars,” he wrote. Breitner doubts any company would sponsor it.

Wolozin agrees the expense would be prohibitive. “We have to pick and choose how we spend research dollars,” he told Alzforum. A prospective clinical trial for statins would have to run for a long time and is likely to have only a small effect. “I don’t consider that a good use of funds, particularly given that we already know we should take statins for cardiovascular disease.” People should be cautious taking these drugs solely to prevent Alzheimer’s, because lowering cholesterol too much may be bad for cognition, he pointed out.

Wolozin speculated that epidemiological studies on statins consistently find a positive effect on AD risk because participants take the drugs over a long period, sometimes from middle age, during which time they maintain cerebral blood flow and perhaps reduce levels of amyloid. In contrast, treatment trials enroll people with or close to dementia, in whom blood flow is already compromised and amyloid has built up. “Statins do not miraculously open up the blood vessels, nor do they get rid of amyloid. They are good at keeping the system healthy, not at switching the system once it is unhealthy.”—Gwyneth Dickey Zakaib

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  1. This appears to be a carefully conceived and conducted prospective observational study of the relation between low- vs. higher-usage of the common statin drugs and incident Alzheimer’s dementia (AD). The study incorporates some clever design features, e.g., establishing exposure classification before the risk period for the outcome of AD diagnosis.

    It exemplifies the usual strengths and limitations of large-scale, database-driven research of this kind. Numbers are large, inviting a comparison of the “effect” of high vs. low statin exposure for all the commonly used statin medicines, and also permitting sub-analyses of “effect” segregated by sex and a number of racial and ethnic categories.

    But we must bear in mind that a larger observational study is no less vulnerable to systematic bias or confounding than a smaller one. Here, the apparent “effect” of statin exposure is relatively small, about 10 percent lower incidence of AD among the higher statin use groups. While still important from a public health perspective, this sort of risk modification can be particularly vulnerable in observational studies to subtle residual confounding from many sources, and it should therefore be interpreted with circumspection.

    The differences in AD incidence by ethnic groups recapitulate earlier findings, but again, because the differences in rates are quite small, it is difficult to interpret these differences either by total or by individual agent statin usage.

    The data do show that AD rates are higher in nonusers of statins than in either the low-use or high-use groups. This tends to support the idea that statin use is protective against AD, but the authors are careful to note the many possible sources of confounding (especially confounding by indication) in this last comparison.

    One puzzling finding is the lack of much if any difference in statin “effects” between lipophilic vs. hydrophilic agents; one might have expected lipophilic agents to be more potent as AD preventives because of their likely blood-brain barrier penetration. This point is obscured somewhat, however, by the fact that hydrophilic agents were much less commonly used in the exposure interval (2006-08) than they are today, resulting in wider confidence intervals in their analysis.

    The relatively small risk reduction reported here in the high- vs. low-use groups may explain some of the difficulties encountered by the randomized trials that have been carried out to test the statin prevention hypothesis. Vast numbers of individuals with lengthy follow-up would be needed to accumulate sufficient statistical power to demonstrate an effect of this size in a condition such as AD with an incidence rate near 1 or 2 percent. This paper may therefore help clarify some of the conflicting literature about the statin—AD relationship and, in particular, the failure of several trials to show a significant benefit of these drugs.

    I am afraid we won’t be able to establish more definitively the effect of statins using trials. With an effect size so small, it would require huge numbers of enrollees and cost tens of millions of dollars. I doubt anyone will sponsor that, given the vulnerabilities of the methodology to date.

  2. This is an interesting article. We have demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) is constitutively present in the hippocampus (Roy et al., 2013; Corbett et al., 2015), and that PPARα serves as a receptor for statins for its non-canonical functions, such as neurotrophin synthesis (Roy et al., 2015).

    Since neurotrophins play an important role in the Alzheimer’s disease process, and since we have also shown that simvastatin is unable to protect memory and learning in an AD animal models lacking PPARα (Roy et al., 2015), it is therefore possible that patients who see no benefit from statins may have less PPARα in their hippocampi.

    References:

    . Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor α. Cell Rep. 2013 Aug 29;4(4):724-37. Epub 2013 Aug 22 PubMed.

    . Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8445-50. Epub 2015 Jun 15 PubMed.

    . HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metab. 2015 Aug 4;22(2):253-65. Epub 2015 Jun 25 PubMed.

  3. This somewhat disappointing report does not adequately take into account decades of research. The clinical trials recommended by the authors have already been conducted, and they have quite thoroughly answered the question of whether statins reduce dementia and cognitive loss. They do not. Further, the paper highlights the continuing lack of understanding of the difference between association and causation.

    The clinical trials needed to address these issues have been done and published. Specifically, the administrative data set published here reflects the use of statins most likely for the treatment of hypercholesterolemia and risk of cardiovascular disease. This data set does not enable a determination of whether the untreated actually should have been treated because they had risk. This is in part because information such as cholesterol levels is unavailable.

    The study did find a reduced risk of AD with high use of simvastatin /therapeutics/simvastatin (as well as the other statins), and the authors suggested that a similar reduction may not have been seen in previous studies because people with dyslipidemia, who may have most benefited from statins, were excluded. However, there is an ethical dilemma in conducting placebo-controlled trials that require withholding an approved treatment from people who should receive the medication for a different indication.  

    Others have conducted studies of patients with dyslipidemia that measured cognition, and they found great cardiovascular protection without an effect on cognition. These studies included thousands of people and were highly published years ago (see Heart Protection Study Collaborative Group, 2002; Shepherd et al., 2002). 

    The present study reinforces the general medical advice of treating a person’s treatable conditions. In this case, if you have dyslipidemia or other risk factors for poor cardiovascular outcomes, treat those conditions. I suspect that if you are not treating those conditions, you are medically underserved, and being medically underserved is a source of bad medical outcomes across the board, dementia among them. In essence, we are not talking about a drug effect of statins on dementia as much as about an effect of inadequate care on multiple bad outcomes.

    References:

    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.

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

  4. This interesting article provides additional hope that the cholesterol-lowering statins may help reduce the risk of AD. Unfortunately, as others pointed out, results from clinical trials with statins for AD have been disappointing.

    However, it is worth noting that as potent inhibitors of HMG-CoA reductase in the mevalonate pathway, statins also inhibit the production of isoprenoid intermediates in addition to the final product cholesterol. The short-chain lipid isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl PP (GGPP), serve as lipid donors for a post-translational process called protein prenylation, catalyzed by farnesyltransferase and geranylgeranyltransferases, respectively. The isoprenyl groups facilitate anchoring of proteins in cell membranes and mediate protein-protein interactions. Prenylated proteins, including small GTPases comprising the Ras superfamily along with heterotrimeric G-proteins, are involved in regulating diverse cellular processes, including synaptic and cognitive function (Hottman and Li, 2014).

    Many of the pleiotropic effects of statins have been shown to be mediated through the reduction of isoprenoids and inhibition of protein prenylation. Importantly, we have demonstrated that the two protein prenylation pathways play distinct roles in AD (Cheng et al., 2013). Reducing protein farnesylation rescued cognitive function as well as attenuated amyloid pathology and neuroinflammation whereas reducing protein geranylgeranylation failed to produce cognitive benefits in a mouse model of AD (Cheng et al., 2013). Depending on the type, dose, and treatment duration of statins, the two prenylation pathways can be affected to different degrees (Winter-Vann and Casey, 2005), which may lead to inconsistent outcomes.

    The role of isoprenoids, protein prenylation, and related downstream signaling pathways in AD is markedly underexplored but could be extremely important mechanistically and therapeutically. The levels of FPP and GGPP are increased in brains of patients with AD. This could potentially disrupt the give-and-take balance between prenylated Ras, RhoA and Rac1, impacting synaptic plasticity (Eckert et al., 2009). 

    Our recent studies with human brain tissue show that dysregulation of protein prenylation occurs in early stages of AD and is associated with cognitive impairment and neuropathology (unpublished). A better understanding of the distinct roles of the two protein prenylation pathways in AD is necessary in order to develop more specific and effective therapeutics for AD beyond statins.

    References:

    . Farnesyl Transferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer's Disease. J Biol Chem. 2013 Oct 17; PubMed.

    . Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol Dis. 2009 Aug;35(2):251-7. PubMed.

    . Protein Prenylation and Synaptic Plasticity: Implications for Alzheimer's Disease. Mol Neurobiol. 2014 Jan 5; PubMed.

    . Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer. 2005 May;5(5):405-12. PubMed.

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References

News Citations

  1. Statins—New Data Suggest Benefits for AD/PD

Therapeutics Citations

  1. Simvastatin
  2. Atorvastatin

Paper Citations

  1. . Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. PubMed.
  2. . Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005 Feb;62(2):217-24. PubMed.
  3. . Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010 Mar 23;74(12):956-64. PubMed.
  4. . A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011 Aug 9;77(6):556-63. PubMed.

External Citations

  1. AlzRisk assessment

Further Reading

Papers

  1. . Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract cholesterol efflux to high-density lipoprotein. Cardiovasc Drugs Ther. 2015 Feb;29(1):7-14. PubMed.
  2. . Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Res. 2011 Jan 31;1371:161-70. PubMed.

Primary Papers

  1. . Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease. JAMA Neurol. 2016 Dec 12; PubMed.