Is it possible for a medication both to increase and to decrease dementia risk? In the case of statins, this can appear to be true. Overall, the beneficial effects of statins seem to outweigh their small risk of interfering with cognitive functioning, but we can’t ignore the many reports of memory impairment associated with these medications. How can this be? There is evidence both for statin-associated brain protection and for statin-associated cognitive interference…and there is a credible explanation.
Evidence for Statins Decreasing Risk of Dementia
Statins are among the most frequently prescribed medications in the United States. Nearly one in three US adults age 40 and older is prescribed a statin. The benefits linked with these medications are very important in fighting cardiovascular disease, which remains our leading cause of death. Statins lower low-density lipoprotein cholesterol and triglycerides. They increase high density lipoprotein cholesterol, also known as the “good” cholesterol. Statins have been convincingly shown to reduce the risk of atherosclerotic heart disease and ischemic stroke.1
In addition to their cardiovascular benefits, statins appear modestly to reduce the risk for developing Alzheimer’s dementia. Evidence for this effect is not consistent. Some large studies find no benefit, while others demonstrate an effect important enough to grab our attention. The most recent carefully designed review and analysis conclude that AD risk is diminished with statin use, attributing the earlier disagreements to differing approaches that researchers took in gathering and understanding their results.2 In addition, a recent large high-quality prospective study supported the benefits of statins for reducing AD risk and this study deserves our notice because it was a well-controlled, randomized investigation that evaluated dementia and statin use among over 3,000 older adults every two years for an average of 6.1 years. The researchers concluded that statin use was protective against AD in those adults under 65, though it appeared slightly to increase AD risk in adults over 80 years old.3
That’s great news, but what about the reports of cognitive problems linked with statin use?
Evidence for Statins Increasing Risk of Dementia
Alarming case reports began to accumulate in the early 2000’s. A description of 60 case reports, published in 2003, advised taking concerns about statin-related cognitive impairment seriously, though cognitive adverse responses were most likely uncommon.4 Simvastatin, atorvastatin, and pravastatin were the medications taken by the patients who were described. About half of these patients noticed cognitive problems within two months of starting treatment. The symptoms improved after drug discontinuation in about half of those affected, which is different from what would be expected of a person with Alzheimer’s disease, which is a progressive condition.
The link between cognitive symptoms and statins, furthermore, is supported by a couple of additional lines of evidence: first, some patients with this problem who noted improvement after stopping their statin medication experienced a recurrence when the medication was restarted.4 Second, a couple of small but well-designed experimental double-blind, placebo-controlled trials associated poorer performance on neuropsychological tests with the use of statins.5,6 In a description of statin effects on a couple of affected patients, the authors reminded us that a cognitive effect which looks small on neuropsychological testing can cast a much larger shadow over actual day-to-day functioning.7
How Can Statins Both Increase and Decrease Risk?
A group of researchers from Denver have recently tried to explain how statins could be both helpful and harmful.1 They note that statins, like other medications that affect metabolism in complex ways, act through more than one mechanism. Statins decrease cholesterol, and that may be an important reason for their cardiovascular benefits. Statin use reduces stroke risk and their cerebrovascular benefits may be important in reducing dementia. There may be additional effects beyond cholesterol reduction as well. Studies have suggested that atorvastatin, for example, can reduce β-amyloid production, reduce vascular inflammation, protect endothelial cell function and reduce brain ischemia.
But cholesterol is also an important structural component of the brain, enhancing brain function in multiple ways. Among other positive actions, cholesterol supports myelin sheath formation which protects brain cells and improves their functioning, supports mitochondrial function and promotes synaptic activity. Too great a reduction of brain cholesterol with statins that enter the central nervous system might deprive the brain of cholesterol’s beneficial effects. Given this possibility, it makes sense that the cognitive problems associated with statins may be more likely to develop in people whose brains are exposed to a higher statin level. This can result from taking a higher statin dose or having less efficient metabolism of the medication. Some researchers suggest that the statins that more easily enter the brain because of their greater fat-solubility (lipophilicity) are more likely to affect cognitive functioning. Atorvastatin and simvastatin are lipophilic statins.1
- Alzheimer’s Disease Toolkit (Helpful Information to Understand and Manage Alzheimer's Disease)
- Expert Information on Alzheimer's Disease (Articles)
- What is Dementia? (Article)
- What Causes Dementia? (Article)
- Medical Conditions that Can Mimic Dementia (Article
- "Is It Something I'm Taking?" Medications That Can Mimic Dementia (Article)
- Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Translational Neurodegeneration 2018. https://doi.org/10.1186/s40035-018-0110-3
- Hersi M, Irvine B, Gupa P, et al. Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence. NeuroToxicology 2017;61:143-187.
- Li G, Shofer JB, Rhew IC, et al. Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc 2010; 58 (7):1311-7.
- Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: Analysis of 60 case reports and review of the literature. Pharmacotherapy 2003;23(7):871-880.
- Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000;108:538-46.
- Muldoon MF, Ryan CM, Sereika SM, et al. Randomized trial of the effects of simvastatin in cognitive functioning in hypercholesterolemic adults. Am J Med 2004;117:823-9.
- Suraweera C, de Silva V, Hanwella R. Simvastatin-induced cognitive dysfunction: two case reports. J Med Case Rep 2016;10: 83. Published online 2016 Apr 5. doi: 10.1186/s13256-016-0877-8
This content was last updated on: November 10, 2020
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