Cardiovascular diseases are becoming increasingly prevalent among the elderly, with 17.9 million deaths attributed to them in 2016, accounting for 31% of global deaths, as reported by the World Health Organization (WHO) (1). The incidence of cardiovascular disease is rising worldwide and poses a significant economic and social burden. Patients with cardiovascular and cerebrovascular diseases often require long-term medication therapy to lower their LDL-C cholesterol levels (38–39). Statins are recommended as first-line agents for adults with LDL-C levels greater than 190 mg/dl and diabetics with levels ranging from 70–190 mg/dl, as they have a low risk of adverse events and are effective in primary prevention of cardiovascular disease (40–42).
The standardized use of lipid-lowering drugs remains a topic of debate due to potential bias from study design in epidemiological studies, which can only establish correlation without elucidating temporal order or causality (27–28). In this study, the use of MR methods revealed causal relationships more accurately, without considering potential bias from study design. Our conclusion is consistent with previous high-quality meta-analyses. Using two sets of genetic instruments and excluding confounding factors, genetic evidence indicated no causal effect of statins on AD (AD) development (36–37). Furthermore, we found no significant causal relationship between statin or ezetimibe alone and the incidence of AD. Our results remained unchanged when considering the combination of cholesterol-lowering therapy. Carlos et al. demonstrated in a narrative review that most of the evidence for cognitive impairment caused by lipid-lowering drugs comes almost entirely from case reports (43). Although these case reports help identify potential clinical drug risks, they are limited by their observational nature, and it is important to interpret these reports accordingly (43). It is worth noting that the benefits and risks of statin use have been well established in several large-scale clinical cohort studies, showing a significant reduction in cardiovascular events, especially when used for secondary prevention (44–45). Currently, no large-sample clinical studies have found that statins can further impair existing cognitive impairment. Data from animal models and limited human data suggest that statin use may have cognitive benefits. The specific mechanism may be related to lowering plasma cholesterol levels, inhibiting cerebral vascular plaque formation, as well as non-cholesterol-related pathways such as alleviating endothelial dysfunction, increasing endothelial nitric oxide generation, anti-inflammatory effects, and antioxidant effects (23.25).
Regarding ezetimibe therapy, there are currently no reports of potential cognitive impairment effects. Existing research suggests that it may prevent further deterioration of cognition in rats with hyperlipidemia or AD rats, but more evidence is needed to determine its specific impact on cognition (18–19). PCSK9 inhibitors are the latest class of cholesterol-lowering drugs. A study conducted on a new monoclonal antibody against PCSK9 (LY3015014) showed that it did not have a significant impact on cognitive function when compared to placebo controls. However, the study was short-term in nature. Another ongoing prospective study included over 2,000 participants who were taking statins and PCSK9 inhibitor (evolocumab). However, no significant differences in cognition were observed during a series of cognitive tests, even when LDL-C levels reached the lowest point (below 0.65 mmol/L) for some participants (46–47). Olmastroni et al.'s systematic review also suggested that the benefit-harm balance of cholesterol-lowering drugs is generally favorable (42). In addition, lifestyle factors such as obesity, long-term smoking, alcohol abuse, and educational attainment may play more important roles in triggering AD compared to cholesterol-lowering therapy alone, but strong clinical evidence is still lacking (10–13).
However, there are still some key factors to consider when explaining the association between lipid-lowering drugs and AD. The first factor is the clinical significance of study results. For example, in one study, users of statins had a corrected Mini-Mental State Examination (MMSE) score of 93.7 compared to non-users who had a score of 92.7. Although these results were statistically significant, the difference was clinically irrelevant (48). The second factor to consider is the quality of studies involved. Multiple systematic reviews have shown that studies involving the effects of statins on cognitive impairment or AD are mostly observational or retrospective studies, and randomized controlled trials and stronger evidence are needed to determine their potential risks or benefits (41–42). Thirdly, statins or other lipid-lowering targeted drugs have not yet been explicitly approved by the FDA or Health Canada for the prevention or treatment of cognitive impairment.
In the past, LDL-C was considered a biomarker for cognitive impairment (49); however, current evidence suggests that normal doses of statins alone do not lead to very low LDL-C levels in the central nervous system due to the protection of the blood-brain barrier, which is maintained by cholesterol-like hormones and bile acids produced by the body (50–51). We also conducted an analysis on whether different lipid-lowering drugs that act on LDL-C causally induce AD. Interestingly, our results showed that the odds ratio (OR) values were very close to 1. Based on MR associations of both the drug itself and the drug targets with AD, neither of them were found to be significant, further confirming that the pharmacological effect of cholesterol-lowering therapy is unlikely to induce or aggravate the development of AD. It is worth noting that previous animal experiments have even found that users of PCSK9 inhibitors may have an increased risk of developing AD, suggesting that PCSK9 dysfunction may result in brain β-amyloid protein production and neuronal cell death, serving as a biomarker for AD (26). Therefore, in addition to reliable clinical evaluations of traditional statin drugs, we should not ignore the interaction between new lipid-lowering drugs and AD, as well as the potential cognitive impairment they may induce. Finally, it should be noted that although cognitive impairment is a rare side effect of lipid-lowering drugs, the clinical use by a large number of patients can amplify rare adverse reactions hundreds or thousands of times over. Therefore, standardized use of lipid-lowering drugs requires long-term follow-up investigations, observational trials, and randomized controlled trials with specific designs.
Our study has several limitations. Firstly, we were unable to directly analyze the causal relationship between the use of PCSK9 inhibitors and the incidence of AD due to the lack of related GWAS data. Secondly, MR analysis is limited by the population from which genetic data is obtained; therefore, our findings may not be representative of the entire British or European population, and there may be racial genetic differences between populations. Thirdly, some subgroups of SNPs for statin drugs have small sample sizes, which may not provide accurate correlations. Finally, since different types of statin drugs have varying pharmacological mechanisms and limited ability to cross the blood-brain barrier, our findings may not capture all tissue-specific relationships for all types of statin drugs.