The Alzheimer's Association reported that in 2013, 5.2 million Americans, including 32% of those age 85 years or older, have Alzheimer's disease. In addition, MCI affects 10% to 20% of those age 65 years or older. If statins were to meaningfully impact the risk of cognitive impairment or dementia (either by increasing or decreasing risk), the potential public health implications could be enormous. Considering the proportion of the population receiving statins, uncommon adverse effects have the potential to impact a large number of people. For example, it was estimated that in 2002, 7.8% of the Canadian population was taking a statin. If the incidence of statin-associated cognitive impairment were only 0.1%, it would currently affect about 2500 people in Canada. In the United States, between 2005 and 2008, approximately 41% of adults 45+ years of age reported using a statin, which represents approximately 126 million people (based on 2010 census). In turn, if 0.1% of these users developed some form of cognitive adverse effect, it would affect 126,600 people. Based on the new American Heart Association/American College of Cardiology Guidelines, the proportion eligible for statins will be even higher. Questions regarding potential cognitive side effects of statins need to be carefully reconciled with the high incidence and prevalence of cognitive impairment from other causes.

Previous studies have indicated that statins use is associated with risk of dementia, but presented controversial results. Medline, Embase, Web of Science, and the Cochrane Database were searched update to November 2017 to identify the potential relationship between statins use and dementia. Thirty-one eligible studies involving a total of 3332,706 participants with 184,666 incident cases were included in this meta-analysis. Statins use was associated with dementia risk decrement (relevant risk [RR]: 0.85; 95% confidence interval [CI], 0.80-0.89). Subgroup analysis showed statins use was associated with Alzheimer disease (AD) (

Rr: 0.81; 95% CI, 0.73-0.89) and non-AD dementia (

Rr: 0.81; 95% CI, 0.73-0.89) risk decrement. Furthermore, statins use was associated with dementia risk decrement in female (

Rr: 0.89; 95% CI, 0.80-0.98) and male (

Rr: 0.88; 95% CI, 0.83-0.93). In addition, a dose-response showed per 1 year of duration of statins use incremental increase was associated with 20% dementia risk decrement (

Rr: 0.80; 95% CI, 0.73-0.87), and per 5-mg mean daily dose incremental increase in statins use was associated with 11% dementia risk decrement (

Rr: 0.89; 95% CI, 0.83-0.96). Statins use was associated with dementia risk decrement. The potency and the cumulative duration of statin utilized played critical roles.

Aims: As the potential impact of statins on cognitive decline and dementia is still debated, we conducted a meta-analysis of observational studies to examine the effect of statin use on the risk of Alzheimer's disease (AD) and dementia.

Methods And Results: PubMed, Cochrane, and EMBASE were searched since inception to January 2021. Inclusion criteria were: (i) cohort or case-control studies; (ii) statin users compared to non-users; and (iii) AD and/or dementia risk as outcome. Estimates from original studies were pooled using restricted maximum-likelihood random-effect model. Measure of effects were reported as odds ratio (OR) and 95% confidence intervals (CIs). In the pooled analyses, statins were associated with a decreased risk of dementia [36 studies, OR 0.80 (CI 0.75-0.86)] and of AD [21 studies, OR 0.68 (CI 0.56-0.81)]. In the stratified analysis by sex, no difference was observed in the risk reduction of dementia between men [OR 0.86 (CI 0.81-0.92)] and women [OR 0.86 (CI 0.81-0.92)]. Similar risks were observed for lipophilic and hydrophilic statins for both dementia and AD, while high-potency statins showed a 20% reduction of dementia risk compared with a 16% risk reduction associated with low-potency statins, suggesting a greater efficacy of the former, although a borderline statistical significance (P = 0.05) for the heterogeneity between estimates.

Conclusion: These results confirm the absence of a neurocognitive risk associated with statin treatment and suggest a potential favourable role of statins. Randomized clinical trials with an ad hoc design are needed to explore this potential neuroprotective effect.

Although concerns regarding a potential adverse impact of lipid-lowering agents on cognitive function have been raised, several lines of evidence point against this association, as detailed in a 2018 European Atherosclerosis Society Consensus Panel statement (150). First, there are three large randomized trials of statin versus placebo where specific cognitive tests were performed, and no differences were seen between statin and placebo (151–154). In addition, no change in cognitive function has been reported in studies with the addition of ezetimibe (112) or PCSK9 inhibitors (115,155) to statin therapy, including among individuals treated to very low LDL cholesterol levels. In addition, the most recent systematic review of the U.S. Food and Drug Administration’s (FDA’s) postmarketing surveillance databases, randomized controlled trials, and cohort, case-control, and cross-sectional studies evaluating cognition in individuals receiving statins found that published data do not reveal an adverse effect of statins on cognition (156). Therefore, a concern that statins or other lipid-lowering agents might cause cognitive dysfunction or dementia is not currently supported by evidence and should not deter their use in individuals with diabetes at high risk for ASCVD (156).