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Statins are a type of medicine that mainly act by lowering the amount of cholesterol in your blood. Cholesterol is the fatty substance that builds up in blood vessels over time, making them narrower, raising blood pressure and increasing your risk of cardiovascular problems. However, statins have other less well-understood effects that may be beneficial during human ageing. For example, statins can reduce inflammation, rebuild telomeres and activate certain longevity-related genes.
That all sounds great – based on what we know about the biology of ageing, we might expect statins to slow the progression of all kinds of age-related diseases. Age-related cognitive impairment and dementia are some of medicine’s most elusive targets, and there’s some evidence that statins may reduce dementia risk. Yet people taking statins sometimes report that the drugs affect their cognitive performance, even causing confusion and memory loss. Is this true, and how is it possible? Can the same drug really protect the brain and impair cognition at the same time?
What does science have to say about statin use and cognitive impairment? It’s a mixed bag. Let’s take the example of atorvastatin, the most commonly used statin. During phase I clinical trials, some healthy people experienced cognitive side-effects like mental confusion, and these side effects got worse with increasing dose. However, in larger phase II and phase III trials, there was no statistically significant relationship between these symptoms and atorvastatin. Despite this, post-marketing surveillance kept finding cases of people who experienced short-term memory loss following statin treatment, which went away when treatment stopped and recurred when treatment was resumed.
Clinical trials are the gold standard for determining whether a treatment causes a certain outcome. However, even the largest clinical trials might not have enough participants to resolve a sufficiently rare side effect. Also, while trials of atorvastatin may disagree with these case reports, trials of some other statins support a significant effect on cognition. For example, several studies suggest that lovastatin results in impaired learning ability in comparison to a placebo treatment. However, these trials were relatively small – about 300 subjects in each. Studies in animal models have also reported that statins reduce the formation of new connections in the brain and impair learning.
OK, so the evidence is mixed. What about the effects of statins on Alzheimer’s risk? Researchers once thought that statins might increase the risk of Alzheimer’s, but this concern has since been flipped on its head. Multiple meta analyses have come out in favour of a link between statin use and reduced risk of dementia, including Alzheimer’s. This one, for example, looked at data from 30 observational studies totalling over 9 000 000 participants. They found that statin use was associated with a 17% reduced risk of dementia from all causes. Another found a much greater risk reduction of 32%.
Observational studies like this can’t prove cause and effect – for that we need randomised, placebo-controlled trials. However, most trials look at whether statins can help people who already have mild to moderate Alzheimer’s (rather than prevent it), and generally find that they are not very effective at slowing disease progression, though there may be some benefit.
Despite the lack of trial data on prevention, the idea that statins lower Alzheimer’s risk is still quite credible because they reduce the risk of cardiovascular disease, which is itself a risk factor for Alzheimer’s. Statins might be able to lower Alzheimer’s risk independently of cardiovascular health as well, though that topic requires more research.
Is it really possible for a drug to be bad for cognitive function while simultaneously protecting against a disease of cognitive impairment? It’s going to take more research to solve this quandary, but there are a few theories out there as to what could be going on.
Statins could be good and bad at the same time
Statins are complex drugs whose effects have many different mechanisms behind them. As already discussed, statins have various anti-ageing effects that might be reducing the risk of Alzheimer’s. They also prevent cardiovascular disease, with cardiovascular disease being an important risk factor for dementia. However, remember that the main way they do this is by lowering cholesterol. While too much cholesterol is a bad thing and can promote dementia, cholesterol is still a vital molecule for the brain. Among other things, cholesterol is involved in the formation of new synapses and is a major component of myelin, the insulating substance that wraps around nerve fibres and accelerates the passage of electrical signals.
Though cholesterol doesn’t easily pass from the blood into the brain, statins can enter the brain and affect cholesterol metabolism therein. By reducing the cholesterol available to the brain, statins could temporarily impair cognition while you are taking them while also protecting against more serious long-term damage, for example due to inflammation.
Statins might not actually impair cognitive function much or at all
As we already covered, there is still disagreement over whether cognitive impairment is a genuine side effect of statin use. Statins have a high nocebo ratio, meaning that a large proportion of side effects (perhaps as high as 90%) are still experienced by people who think they are taking statins, even if they are actually taking a placebo treatment. We also saw that the clinical trial data regarding cognitive impairment is not particularly strong.
The effects of statins are not the same for everyone
It’s likely that certain factors put specific people at more risk of cognitive impairment than others when taking statins – we just don’t have enough data to know what those factors are. For example, people who don’t metabolise statins as quickly, or in whom treatment results in more statins reaching the brain for whatever reason, could be at greater risk. The same can be said of Alzheimer’s risk reduction – we need to do more subgroup analyses (that’s when researchers categorise people by age, sex and so on to study whether a treatment affects them differently). For example, some studies suggest that people below the age of 80 benefit more from statins when it comes to Alzheimer’s risk. Some have proposed that this is because high cholesterol plays a greater role in promoting Alzheimer’s in midlife than in later life.
While there’s still some uncertainty about the effects of statins on cognition and dementia risk, the benefits would seem to outweigh the risks. In the UK, the National Institute for Health and Care Excellence (NICE) believes that it may be worth taking statins as preventative medication, even for people at low risk of cardiovascular disease.
Essentially, the benefits of reducing cardiovascular disease (and potentially other diseases) by even a small amount are deemed to outweigh the risk of side effects. It’s important to note, however, that this may not extend to younger people, among whom the effects of statins are largely unstudied. While very rare, statins can also cause life-threatening reactions in some people.
Title image by Freepik
The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms https://doi.org/10.1186%2Fs40035-018-0110-3
Statins may slow human aging by protecting against telomere shortening: A feature of senescent cells https://www.sciencedaily.com/releases/2013/08/130829112854.htm#
Statins Induce a DAF-16/Foxo-dependent Longevity Phenotype via JNK-1 through Mevalonate Depletion in C. elegans https://doi.org/10.14336%2FAD.2019.0416
The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis https://doi.org/10.1007/s11938-018-0180-4
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Simvastatin impairs hippocampal synaptic plasticity and cognitive function in mice https://doi.org/10.1186/s13041-021-00758-x
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Age-varying association between statin use and incident Alzheimer's disease https://doi.org/10.1111/j.1532-5415.2010.02906.x