Wednesday April 4 2012
Claims statins halt Alzheimer's are based on research in mice
Cholesterol-lowering statin drugs “could stave off the symptoms of Alzheimer’s”, according to The Daily Telegraph. The front page of the Daily Express even boldly reported: “Statins halt Alzheimer’s.”
These attention-grabbing claims could easily lead readers to assume there has been a major breakthrough in the fight to cure Alzheimer’s disease. However, they are based on a small laboratory study that used mice that had been bred to display signs of Alzheimer’s.
The early-stage research showed that the cholesterol-lowering drug simvastatin could improve learning and memory in mice genetically engineered to produce excess levels of amyloid protein in the brain, a characteristic feature of Alzheimer’s disease in humans. However, these improvements were only seen in younger mice, not older ones. The researchers took this to mean that statins would only be effective for blocking early-stage disease. The research also demonstrated that simvastatin caused some improvement in blood vessel function, which some researchers believe to be involved in developing the condition.
Even though these seem like positive results in mice, research has already looked directly at whether statins can stop Alzheimer’s and other forms of dementia in humans. For example, two recent high-quality reviews of research into statins and dementia suggest that there is no evidence that statins provide any specific benefit to humans with Alzheimer’s. While the new research suggests that the timing of statin use may allow it to have an effect, the evidence is far from conclusive and this would need to be explored further in a laboratory. Given the limitations of this research and the uncertainty over its results, the headline “Statins halt Alzheimer’s” is wildly misleading.
Dr Simon Ridley, head of research at Alzheimer’s Research UK, has put the study into context in a statement for Behind the Headlines. He said: “People should view the results with caution until further research has teased out how simvastatin might be working in these mice, and more importantly, until there is any significant new clinical trial data in humans.”
Where did the story come from?
The study was carried out by researchers from McGill University, Canada, and was funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. The study was published in the peer-reviewed Journal of Neuroscience.
Newspaper headlines about this research were generally misleading and suggested that it directly applies to humans. Most media reports took a few paragraphs, and in some cases half the article, to inform readers of the key fact that this research was carried out in mice and not humans. While the Daily Express’ headline suggests that statins have been proven to “halt Alzheimer’s”, this is not justified by the newly published research. In fact, the current body of high-quality research on this topic suggests the opposite is true.
What kind of research was this?
This laboratory study assessed the effect of simvastatin on different signs and symptoms of a mouse model of Alzheimer’s disease. Simvastatin is a widely used statin drug that can control levels of cholesterol in the body. Around the world, many millions of middle-aged and elderly people take statins. To date, analysis of these populations has not detected any protective effect of the drug against dementia, including Alzheimer’s.
Laboratory studies in mice represent the early stages of medical research. During these mice-based studies, researchers are able to manipulate mice into displaying key characteristics of human disease, which they can then study in detail to better understand the condition in humans. For example, mice may be genetically modify to have biological characteristics similar to a human disease. However, there are key differences between mice and men and early, experimental results from studies in mice may not always translate into similar findings in humans.
Alzheimer’s disease is characterised by the presence of deposits of the protein beta-amyloid in brain cells. These deposits are also known as amyloid plaques. These can interfere with the normal functioning of brain cells, causing the symptoms of memory loss and other deterioration in cognitive function commonly associated with Alzheimer’s disease. The authors of this study also said that Alzheimer’s is associated with problems in the blood vessels and blood circulation in the brain, and that previous research suggests this compromised blood flow could be related to the progression of Alzheimer’s.
Because statins can help keep blood vessels free of fatty build-up, some people have speculated that they could have a role in preventing Alzheimer’s disease. Previous reviews have not found an apparent link between statins and Alzheimer’s. However, the authors of this new research say recent evidence suggests that the cholesterol-lowering drugs may have beneficial effects on the development and progression of Alzheimer’s disease.
What did the research involve?
This study involved mice that were bred to produce excessive amounts of beta-amyloid protein in their brains, thereby mimicking the key biological characteristic of Alzheimer’s in humans. The research looked at the effect of the statin drug simvastatin on the levels of amyloid in the brain, as well as its effects on blood flow and blood vessel function in the brain.
The study used three main types of mice:
- mice bred to have Alzheimer’s-like disease who received simvastatin (treatment group)
- mice bred to have Alzheimer’s-like disease who didn’t receive simvastatin (control group)
- mice that were not bred to have Alzheimer’s-like disease or receive simvastatin (natural group)
Simvastatin was given to the treatment group mice in their drinking water, while controls were given the same amount of water without the statin. Simvastatin was administered at 20mg per kilo of body weight per day for three days. This was increased to 30mg/kg/day for four days, and then to 40mg/kg/day for the rest of the treatment.
The treatment group was further divided into two age groups: adult and aged. Adult mice were six months old and had been treated with statins from three months of age for a period of three months. Aged mice were 12 months old and had been treated from six months of age for six months. Total cholesterol levels were measured to assess the effect of the statin.
Spatial memory and learning were assessed with a commonly used water maze test. This involves placing a mouse into a small pool of water containing an escape platform hidden beneath the water’s surface. Visual cues indicate its location, and researchers record how quickly the mouse learns the location of the platform on repeated attempts. The visual cues and platform location can be changed to further assess learning and memory.
Three days after they had completed the maze task, mice were anaesthetised and the blood flow in their brains was measured using a standard technique. This involved using lasers to gauge the amount of fluid moving through their blood vessels. In a subset of mice, a small sample of artery blood vessel tissue was taken from their brain and subjected to laboratory experiments. These were designed to assess its ability to contract and relax as a normal functioning blood vessel should.
The researchers then used appropriate statistical analysis techniques to examine their results.
What were the basic results?
The key finding of this study was that simvastatin fully restored short- and long-term memory in adult mice, but not in aged mice. The researchers found that these beneficial effects occurred without a decrease in the amount of amyloid plaque found in the brains of the mice.
In addition, simvastatin restored key aspects of the functionality of the arteries in the brains of mice with Alzheimer’s disease. This functionality was impaired in mice that did not receive the statin.
How did the researchers interpret the results?
The researchers concluded that simvastatin, and possibly other brain-penetrating statins, show “high therapeutic promise” in early Alzheimer’s disease and in patients with vascular disease who are at risk of developing Alzheimer’s disease.
News reports of this research have ranged from optimistic to misleading. The study’s early mouse-based results need to be viewed in context, particularly as no benefit of statin use on Alzheimer’s has been found when directly examined in humans.
This study shows that the cholesterol-lowering drug simvastatin could improve blood vessel function and learning and memory in mice with features of Alzheimer’s-like disease, but only when given “early in the disease process” (when the mice were at a younger age). However, improved performance in a water maze may not necessarily demonstrate reversal of Alzheimer’s, particularly as the researchers found no decrease in the amount of amyloid plaque found in the brains of the mice. This means that even in mice, the statin had no effect on amyloid, a key characteristic in the human form of the disease.
Furthermore, a recent systematic review of the literature on statins and dementia (including Alzheimer’s disease, which is one type of dementia with strict diagnostic criteria) concluded that the use of statins to prevent vascular disease did not appear to prevent Alzheimer’s. It concluded that “there is good evidence [from randomised controlled trials] that statins given in late life to individuals at risk of vascular disease have no effect in preventing Alzheimer’s or dementia”. This review sought to identify all high-quality literature published on the topic, and it is unlikely that these conclusions would change on the basis of the new, small animal study.
Similarly, a systematic review also looked at whether statins were effective at treating dementia, using high-quality studies published before March 2009. It included a study that assessed the effect of simvastatin on Alzheimer’s disease. It too concluded that there was insufficient evidence to recommend statins for the treatment of dementia, including Alzheimer’s.
This research is bound to be of great interest to people with Alzheimer’s disease and their loved ones, particularly given the impression they may have gained from reading newspaper accounts of it. Dr Simon Ridley, head of research at Alzheimer’s Research UK, the UK’s leading dementia research charity, has helped put the research into context in a statement issued to Behind the Headlines. He said: “These kinds of studies, in which some characteristics of Alzheimer’s in mice are prevented or reversed, are often interesting and can help to guide both understanding of the disease as well as future studies in people. While some studies in humans have suggested that statin users may have a lower risk of Alzheimer’s, this has not been consistent.
“However, as with many trials for chronic diseases, there is always the issue of whether there is a critical time to give treatments that offers the best chance of success.
“Although simvastatin is a cholesterol-lowering drug, this study in mice did not explain exactly how simvastatin was having its beneficial effect. Interestingly, there did not seem to be a reduction in cholesterol in the mice treated with simvastatin, suggesting that the drug may be acting through a mechanism independent of its ability to lower cholesterol. Therefore people should view the results with caution until further research has teased out how simvastatin might be working in these mice, and more importantly, until there is any significant new clinical trial data in humans.”
Consequently, while the research may offer scientists some new clues on the development of Alzheimer’s disease, front-page headlines that “Statins halt Alzheimer’s” are not supported by this small animal study or by the weight of existing research on the topic.
Analysis by Bazian