Do statins cause dementia?

The evidence linking statins with short-term cognitive deficits is limited because of the challenges of conducting randomized controlled studies (RCTs) in a population with a high background rate of cognitive changes and statin use. However, some case reports have temporally linked statin use with the occurrence of cognitive decline, like memory loss, within months of starting statins.^1,2 Though these reported events are rare, some of the case reports noted that symptoms of cognitive decline improved when statins were discontinued.^1,3 This information led to warnings in package inserts for statins that cognitive decline may occur.^2,4–10  

Since the benefits of statins have become widely appreciated, millions of people are exposed to statins every year. Nearly 40 million people were estimated to be taking statins in 2013.¹¹ Such a large number of individuals exposed to statins provides reassurance that the number of case reports to date represent extremely rare adverse events, if indeed cognitive decline is caused by exposure to some statins.

Swiger et al. conducted a systematic review and meta-analysis of 16 high-quality RCTs and prospective cohort studies evaluating the effect of statins on cognition among adults without cognitive dysfunction at baseline.¹² In three of the studies, short-term changes in cognition were measured in several ways, the most common of which was digit symbol substitution testing, a well-validated outcome measure that considers multiple cognitive functions, including memory. There was no statistically significant difference between 296 patients taking statins and those taking placebos when measuring the mean change in cognition from baseline to follow-up in the three separate trials.

Some studies examined the effects of specific statins on the incidence of cognitive decline. In one early double-blind investigation, 209 adults with low density lipoprotein C levels ≥160 mg/dL were randomly assigned to receive either lovastatin 20 mg or placebo for six months.¹³ Performance on the cognitive tests between baseline and follow-up was slightly, but statistically significantly, better in the placebo group, although the clinical significance of these small changes is unclear. In a similar study using simvastatin, 283 patients with elevated cholesterol were randomly assigned to take simvastatin 10 mg, simvastatin 40 mg, or placebo, also for six months.¹⁴ As in the lovastatin study, cognitive performance was slightly lower in the simvastatin group compared to the placebo group (p=0.008). Generally, the difference between the treated and untreated groups was that those taking placebo showed improvement in their cognitive scores between baseline and follow-up, presumably because they learned from the first test, while those on simvastatin did not. The baseline cognitive ability of those on statins differed from those on placebo, however, which limits the interpretation of the findings.

In addition to short-term memory loss, some investigations have examined the relationship between statins and long-term cognitive decline or dementia. However, for ethical reasons and because of the overwhelming evidence of the benefits of statin use, high-quality randomized controlled trials measuring statins' long-term effect on dementia are difficult to design. The available evidence does not support a correlation between statin use and dementia. Although the direction of causality is not possible to determine, some studies have suggested that statin use may have a beneficial effect.^13,14

One cross-sectional study using hospital records found 60% to 73% lower rates of probable Alzheimer’s disease among patients taking statins compared to those in the entire population, and those taking other (non-statin) medications for the treatment of hypertension and cardiovascular disease.¹⁵ Jick et al. conducted a case-control study comparing 284 patients with dementia with 1080 controls.¹⁶ The adjusted relative risk of dementia among persons taking statins was 0.29 (95% confidence interval [CI] [0.13 – 0.63], p=0.002) compared to relative risk for people with untreated hyperlipidemia (odds ratio [OR] 0.72, 95% CI [0.45 – 1.14]) and for people treated with non-statin lipid-lowering agents (OR 0.96, 95% CI [0.47 – 1.97]), suggesting that the use of statins may actually lower the likelihood of dementia.     

To measure the long-term effect of statins, Swiger et al. analyzed data from 23,443 patients taking statins for 3 to 24.9 years.¹² Three of the studies included in the analysis found no association between statins and dementia, while five found a beneficial effect. Pooling the results of all studies results in a 29% decrease in incident dementia in patients taking statins compared to placebo (hazard ratio 0.71, 95% CI [0.61 – 0.82]). In this analysis, all statins were considered together, so it is not possible to draw conclusions about differences in effects among individual statins.

Two other large studies that measured long-term effects of statins also found no significant differences between those taking statins and the control group with respect to the incidence of dementia.^17,18 The PROSPER study of 5804 elderly men and women treated with statins for three years measured cognitive function with four separate tests (the Mini-Mental Status Exam, the letter-digit coding test, the picture-word learning test, and the Stroop test) and found no statistically significant differences in cognitive decline between statin-users and controls.¹⁸ In the Heart Protection Study of 20,536 participants, the authors conducted a secondary analysis with a Telephone Interview of Cognitive Status when the study was completed, and again after a mean of 5.3 years.¹⁷ Again, there was no difference between treatment and control patients.

In summary, observational studies and randomized controlled studies have attempted to establish or refute a causative relationship between statins and dementia.¹⁹ To date, these studies have not been able to prove that statins increase the risk of developing dementia and some studies suggest that statins may actually decrease the risk.^12,20–22

The American College of Cardiology/American Heart Association guidelines for management of blood cholesterol consider the risk of memory or cognition side effects from statins to be rare.²³ However, because the development of dementia is a long-term progressive phenomenon, it is not possible with existing evidence to rule out the possibility of an association with statin use.

^References

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