Do Statins Increase or Decrease the Risk for Dementia?

Christopher Labos, MD, CM, MSc


July 28, 2021

The other day I was emailed a link by a long-time statin user, concerned about reports that statins increase the risk for dementia. Unfortunately, stories that statins can cause dementia or memory loss have been with us almost since the drugs were first put on the market. In fact, worries that cholesterol-lowering medication could affect brain function predate statins by decades and seem to reappear with minor modifications every few years or so. But the real reason why such reports should not cause undue worry is that they rely on something that has led many researchers down blind alleys over the years: surrogate endpoints.

Interestingly, the worry that cholesterol might affect neurocognitive function dates back to one of the earliest cholesterol trials, the Coronary Primary Prevention Trial, which tested cholestyramine vs placebo. While the drug was associated with reduced cardiovascular events, there was also an increased risk for violent death by suicide, accident, or homicide. Some worried that statins were reducing cholesterol levels to such a degree that there was insufficient cholesterol left for brain cells to function normally, leading to increased rates of depression or altered behavior, and therefore suicide or accidental death. Why this would make one more prone to death by homicide was never entirely clear.

So it was not surprising that when statins were introduced, the same types of concern would materialize. Amazingly, there has been quite a bit of research on this topic, though not all of it is consistent. The randomized trials done with statins have not suggested any increased risk for dementia or memory loss, but it is true that rare side effects might not be detected by randomized trials. If you run a study with 10,000 participants, then you might miss a one-in-a-million side effect. The way around this is with postmarketing surveillance studies, which assess the impacts of medications in the broader population. When you have data on millions of people taking a medication, you can detect even rare side effects.

Unfortunately, studies such as these are not randomized trials, so the people who take statins are fundamentally different from the people who do not. They may take other drugs, they may have concurrent diseases, and they probably have different lifestyles. In randomized trials, these differences tend to balance out, but in observational research, such differences are hard to account for, even with advanced statistical techniques.

So when observational studies show a link between statin use and dementia, you always have to ask: Is this a true causal link or is it simply that people prescribed statins tend to be older, and older patients are more likely to get dementia? Teasing out such distinctions is never easy and probably explains why results in this area have been so variable. For every study suggesting a link, we have another, such as the recently published analysis by Zhou et al showing no association between statin use and dementia, mild cognitive impairment, or cognitive decline.

In fact, there is good reason to think that the opposite would be true, that statins could prevent at least one form of dementia. We tend to lump all dementia types together and sometimes, rather erroneously, refer to everything as Alzheimer’s disease. In reality, Alzheimer’s disease is just one disease that can cause dementia; other pathologies, like Lewy body dementia, frontotemporal dementia, or vascular dementia, could be responsible. A large stroke, or more commonly a series of small strokes, can also lead to decreases in cognitive function. Statins have been shown to decrease the risk for stroke, and so it seems to be a very reasonable assumption that by preventing strokes, especially the small repetitive strokes that accumulate over time, you would prevent the onset of dementia.

While logical, the evidence is not conclusive, and whether statins are beneficial, harmful, or have no effect on dementia risk is still uncertain. However, whenever you have multiple studies with differing results, the final conclusion is generally that there is no large effect one way or the other.

So it was with some skepticism that I looked over the link I was sent. I found that it was referring to a conference presentation at the Society of Nuclear Medicine and Molecular Imaging Annual Meeting. Researchers used PET scans to identify differences in brain metabolism between statin users and non-users. While there is nothing wrong with conference presentations, they are often preliminary analyses of research work that might, and often do, change substantially when finally published in a peer-reviewed journal.

More importantly, though, the researchers were primarily looking at findings on PET scans and not testing the participants' cognitive function. You need to be cautious when using surrogate endpoints like this. Surrogate endpoints can be useful in medical research but they can also lead you astray. It might be reasonable to look at whether a medication lowers blood pressure, but what you really care about is whether it prevents heart attacks or stroke. It’s possible, and not unusual, for a treatment to affect a surrogate endpoint, such as blood pressure, without affecting clinical outcomes.

All this is to say that I am not excessively worried about dementia risk with statins. By preventing strokes and other hard cardiovascular endpoints, they are almost certainly doing more good than harm. We will have to see if future evidence tilts the balance one way or the other, but for now, most readers can rest assured that if there is any impact on cognitive function, it is probably small and probably not clinically significant.

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About Dr Christopher Labos
Christopher Labos is a cardiologist with a degree in epidemiology. He spends most of his time doing things that he doesn't get paid for, like research, teaching, and podcasting. Occasionally he finds time to practice cardiology to pay the rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn't know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, CBC Morning Live and CTV television in Montreal.


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