Statins Not Linked to Dementia or Memory Changes: ASPREE

Older patients who are taking statins do not appear to be at an increased risk of adverse neurocognitive changes, including the development of dementia or mild cognitive impairment, according to a new study.

The observational findings, which emerged from an analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, provide reassurance that there is no neurocognitive risk to statin therapy in older patients, say experts.

“Compared with no statin use, baseline statin use was not associated with incident dementia or mild cognitive impairment and their subclassifications,” write Zhen Zhou, PhD (University of Tasmania, Hobart, Australia), and colleagues in their paper, which was published June 21, 2021, in the Journal of the American College of Cardiology. “Nor was statin use associated with changes over time in composite cognition and its components, including global cognition, episodic memory, language and executive function, and psychomotor speed,” they say.

In 2012, the US Food and Drug Administration attached a “black box” for all statin drugs to warn of a possible adverse effect on cognitive performance, although the agency acknowledged that the cardiovascular benefits of the drugs outweigh the risks.   

Seth Martin, MD (Johns Hopkins University School of Medicine, Baltimore, MD), who wasn’t involved in ASPREE, said that concern about the cognitive effects of statins is a question that arises among patients, although it is not something he is overly worried about in his statin-treated patients. In 2013, Martin published results from a large meta-analysis showing that statin therapy had no impact on cognition among people without baseline cognitive dysfunction. In that meta-analysis, long-term follow-up ranged from 3 to nearly 25 years. 

“For my patients, I provide a message of reassurance,” said Martin. “There’s been a lot of work about this issue over the years.”

In one of the most recent deep dives into the data, researchers led by Anish Adhikari, MD (Albany Medical Center, NY), published a meta-analysis of 24 randomized trials and observational studies, including one with nearly 1.5 million subjects, and also found no evidence of adverse cognitive effects with statin use in those aged 60 years and older. There, the longest follow-up was 15 years.

From a big picture perspective, the data are very reassuring. Seth Martin

Neurologist Kelly Sloane, MD (University of Pennsylvania Perelman School of Medicine, Philadelphia), said that while research from the 2000s suggested statins might have a detrimental effect on cognition, a number of later studies have found that the lipid-lowering drugs do not result in any impairment. In fact, some analyses have even hinted that statins might be protective in older adults, she said.

“When I see patients with concerns about cognition and their memory, we generally look at their medications as a source for reversible causes of impairment,” Sloane told TCTMD. “Medication use, and whether they’re on a statin, is considered, but the practice has moved away from thinking about statins as a major contributor to cognitive impairment.”

Sloane, who cares for stroke patients, said the prevention of a second stroke or other cardiovascular and cerebrovascular events must be weighed against the risk of a cognitive deficit with statin therapy.    

Statins and Cognition

The ASPREE study, published in 2018, was a large-scale randomized trial with 18,846 patients (median age 74 years; 56.4% women) testing whether aspirin should be given to the elderly for primary prevention. After 4.7 years of follow-up, treatment with aspirin didn’t reduce cardiovascular outcomes but instead was associated with a significantly higher risk of major bleeding. Comprehensive cognitive data were collected in ASPREE, as survival free from disability and dementia was the primary endpoint of the trial.    

During 85,557 person-years of follow-up, there were 566 incident cases of dementia and 389 incident cases of mild cognitive impairment recorded. Compared with no use, statins were not associated with risks of dementia or mild impairment. Over the follow-up period, there was no difference in the change in cognition—or any of the cognitive domains—between those who were receiving statins and those who were not. The absence of harm was seen in patients treated with hydrophilic statins, such as rosuvastatin, and lipophilic drugs, such as atorvastatin.

Practice has moved away from thinking about statins as a major contributor to cognitive impairment. Kelly Sloane

There was an interaction between baseline cognitive ability and statin therapy for all dementia outcomes. In the analysis, the risks of dementia and changes in episodic memory increased as cognitive scores at baseline decreased. No other interaction was observed, including for age and sex. Additionally, the association between statin use and cognitive outcomes did vary by baseline LDL-cholesterol levels.

Martin said that while the latest ASPREE data are helpful, they will not be the final statement on the topic. There are major ongoing randomized trials—STAREE and PREVENTABLE—that will specifically address statin use in older patients. STAREE researchers are randomizing approximately 18,000 patients older than 70 years to atorvastatin 40 mg or placebo for the prevention of major vascular events, while PREVENTABLE is testing whether atorvastatin 40 mg in 20,000 adults without preexisting disease can reduce the risk of new dementia or disability.

Where Does This Study Leave Us?   

In an editorial, Christie Ballantyne, MD, and Vijay Nambi, MD, PhD (Baylor College of Medicine, Houston, TX), highlight some of the known side effects of statins, including liver function abnormalities, diabetes, muscle pain/weakness, and changes in memory. The risk for serious side effects is low, but muscle pain/weakness and memory changes are important because they affect patients’ quality of life. Thus far, data on statin-associated changes in memory have been “inconsistent,” they write.

The ASPREE analysis, state Ballantyne and Nambi, was “well done,” with one of its strengths being the large number of standardized tests to track cognition and dementia. However, it is a post hoc analysis, and there was no data on statin doses or achieved LDL over time.    

“So where does this study leave us with respect to lipid lowering, statins, and dementia?” they ask. “On the basis of accumulated evidence, lipid lowering in the short term does not appear to result in improvement or deterioration of cognition irrespective of baseline LDL-C levels and medication used. The present study further provides additional information that the lipo- or hydrophilicity of the statin does not affect changes in cognition. However, the potential increased risk for Alzheimer’s disease, especially among patients with baseline cognitive impairment, requires further investigation.”

Sloane said the risk of dementia doubles every 10 years for patients 65 years and older, and the risk of developing it earlier is tied with the patient’s cognitive reserve. Today, resistance to statin therapy has less to do with concerns about cognition than with severe muscle pain or the risk of intracranial hemorrhage, particularly in patients with a prior history of stroke, she said. Yet, “more and more trials are coming out to show that this is not the case,” said Sloane. “There have been a lot of side effects that have been attributed to statins that might not be due to the statin.” 

To TCTMD, Martin said that as patients are started earlier in life on statin therapy to prevent atherosclerotic cardiovascular disease events, this might prove to be beneficial from a neurocognitive standpoint given that they help improve overall vascular health, including in the brain. However, for such a study to address whether statins prevent dementia, it would require decades-long follow-up. STAREE and PREVENTABLE should provide answers to some of the big questions, although the trials will likely raise as many questions as it answers.

“There’s a lot of nuance here,” said Martin. “That’s a different question—starting statins earlier and preventing dementia versus the impact of newly-initiated statin therapy in elderly patients. . . . However, from a clinical perspective, I hope these nuances in the science don’t have a negative effect on patients who would benefit from statin therapy to avoid it. From a big-picture perspective, the data are very reassuring.”