Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, are fundamental in the primary and secondary prevention of cardiovascular (CVD) [1]. Statins are among the most prescribed medications, with nearly 1 in 3 U.S. adults using them [2]. Their popularity is attributed to their efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and CVD prevention [2]. However, despite nearly four decades of use and extensive research, the potential impact of statins on cognition and dementia remains a hotly debated topic [3]. At the same time, cognitive impairment and dementia pose a major public health burden and lack effective treatments [4].

The relationship between hypercholesterolemia and dementia is complex and not fully understood [5]. While midlife hypercholesterolemia is associated with a higher risk of cognitive decline and dementia, late-life hypercholesterolemia does not show the same risk, suggesting that cholesterol exposure duration may play a role [6]. However, life-long exposure to high cholesterol in those with familial hypercholesterolemia is not associated with an higher dementia risk [7]. Even so, the presence of atherosclerosis, which is closely related to hypercholesterolemia, has been associated with increased risk of dementia [8]. Given these findings, there is substantial interest in investigating whether lipid-lowering therapy with statins can help reduce the risk of cognitive impairment [9].

Since the release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of hypercholesterolemia, statin use has continued to rise [2]. These guidelines emphasize the use of high-intensity statins and dose intensification to optimize LDL-C reduction and prevent CVD. But as statin prescriptions have increased, so has interest in their potential effect on cognition [5]. In 2012, the U.S. Food and Drug Administration (FDA) issued a warning about potential cognitive impairment associated with statin use [10]. The data supporting this warning were mostly based on case reports and smaller observational studies [10]. Subsequent research has yielded mixed results, with studies reporting detrimental, neutral, or even protective effects of statins on cognition [11,12,13,14,15,16,17,18]. Notably, concerns about memory loss and cognitive changes are frequently reported as adverse effects of statins, which may discourage their use and potentially deprive patients of the cardiovascular benefits of statins [19]. It has been observed that the use of high-intensity statin therapy and dose intensification remains suboptimal among patients who would benefit from it [2]. Individuals for whom statin therapy is indicated but who do not adhere to it or discontinue treatment due to adverse effects, whether perceived or real, face an increased risk of CVD [20]. Concerns about harmful effect on cognition may undermine acceptance or adherence to statin therapy.

Data from several early studies raised concerns about an increased risk of cognitive impairment and dementia with statin use [12, 14], but more recent epidemiologic larger studies have not supported these findings [21,22,23]. Therefore, the purpose of this review is to examine the current evidence regarding the effects of statins on cognitive function, addressing ongoing debates and uncertainties in the field. While observational studies and smaller clinical trials have had inconsistent outcomes, many have been criticized for methodological issues, including potential biases such as confounding and reverse causation, as well as inconsistencies in the types of statins, dosages, and tools cognitive testing or methods used for the identification of dementia cases [3, 24].

Given the ongoing debate, the results of two well-designed randomized controlled trials (RCTs), STAREE (Study of STAtins for Reducing Events in the Elderly) and PREVENTABLE (Pragmatic evaluation of events and benefits of lipid lowering in older adults), are highly anticipated [25, 26]. These trials, with rigorous designs and comprehensive neurologic assessments, have the potential to provide a clearer understanding of the relationship between statin use and cognition, helping to resolve conflicting findings and guide future clinical recommendations.

Statin Characteristics, Mechanisms and Cognition

Statins lower CVD risk through the reduction of LDL-C by inhibiting the HMGCR enzyme in the liver [27], but they also have anti-inflammatory and antioxidant effects [28]. It remains unclear whether statins have similar effects in the brain and how they might impact cognition [5]. Before examining the existing clinical evidence on how statins may impact cognition in clinical studies, it is important to first recognize the physiological differences between cholesterol homeostasis in the brain and peripheral tissues. The brain contains about 20% of the body’s cholesterol, most of which is metabolically dormant in myelin [29]. Brain cholesterol is synthesized locally by astrocytes, neurons, and oligodendrocytes and remains largely isolated from peripheral cholesterol due to the blood-brain barrier (BBB) [30, 31]. The BBB is impermeable to apolipoprotein B (apoB)-containing lipoproteins, including LDL-C, very low-density lipoproteins, and chylomicrons [31, 32]. Therefore, dietary cholesterol intake has a minimal effect on the level cholesterol in the brain. Furthermore, the amount of cholesterol in the human brain is determined in early development and remains relatively constant throughout adulthood [31]. Brain cholesterol is also metabolized differently compared to peripheral cholesterol. In the brain, a brain-specific pathway involving cholesterol 24-hydroxylase facilitates the metabolism and elimination of cholesterol from the brain [5]. Additionally, unlike peripheral cholesterol, which has a short half-life of hours to days, brain cholesterol is produced slowly and has a long half-life of up to 5 years [31]. As a result, statins can effectively lower peripheral cholesterol, without significantly affecting brain cholesterol levels [33]. Differences between brain and peripheral cholesterol are summarized in Table 1.

Table 1 Comparison of brain cholesterol and peripheral cholesterol

Beside the physiological differences between peripheral and brain cholesterol, the potential effects of statins on cognition may also depend on specific characteristics of each statin. First, statins vary in their ability to cross the BBB according to their lipophilicity, possibly contributing to their differing effects on the brain [5]. More lipophilic statins like simvastatin, lovastatin, and atorvastatin are more likely to cross the BBB than hydrophilic statins like pravastatin and rosuvastatin [34]. However, current evidence is inconsistent regarding whether differences in the lipophilicity of statins influence their effect on cognition [15, 35, 36].

The timing, dosage and dosage-intensification, and duration of exposure to statin therapy have also been reported to influence its effects on cognition [35]. A study found that early statin use, defined as starting statins before acetylcholinesterase inhibitors, was associated with a reduced risk of disease progression in Alzheimer’s disease (AD) [37]. A duration–response relationship has been observed with one study finding a 9% reduction in dementia with each year of statin treatment [38]. Studies on the cognitive effects of statin dose intensification have produced conflicting results [35]. Some research suggests that higher doses of potent statins, like atorvastatin and rosuvastatin, may offer greater neuroprotection [39]. However, other studies have found that high-intensity statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg) have a stronger with cognitive impairment compared to moderate-intensity statins (atorvastatin 10–20 mg, rosuvastatin 10 mg, simvastatin 20–40 mg, and pravastatin 40–80 mg) [40]. The design of future clinical trials needs to include evaluating the impact of statin adherence on cognition, as most observational studies often lack this information.

Several patient factors may influence how statins affect cognition, including genetic factors such as LDL receptor (LDLR) status and apolipoprotein E (APOE) genetic variants [41]. Some evidence suggests that statins may reduce the risk of AD in individuals with the APOE ε4 allele [42]. Statins may also affect cognition through cholesterol-independent mechanisms such as amyloid-β (Aβ) cascade, tau phosphorylation, oxidative stress, apoptosis, neuroinflammation, and synaptic plasticity [43]. The aggregation of Aβ plaques and neurofibrillary tangles are key pathological mechanisms in AD, the leading cause of dementia [44]. There is a discrepancy in the literature regarding whether statins have an effect on the biomarkers of AD. A study found that statin therapy slowed Aβ deposition in cognitively healthy individuals but not in those with clinical signs of cognitive impairment [45]. However, another study showed that the effect of simvastatin on cerebral spinal fluid levels of phosphorylated tau181 in cognitively healthy individuals depends on baseline LDL-C levels [46].

Figure 1 illustrates the potential mechanisms and modifying factors influencing the effects of statins on cognition.

Fig. 1

Potential mechanisms and modifying factors of statins’ effect on cognitive health. Abbreviations. Aβ, amyloid β; CNS, function. APOE4, apolipoprotein E isoform 4; CYP2C9, cytochrome P450 family 2 subfamily C member 9; CYP2P19, cytochrome P450 2 subfamily C member 19; CVD, cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus

Evidence for Negative Effects of Statins on Cognition

The FDA’s decision in 2012 to issue a warning about the potential negative effects of statins on cognition was based on small studies and case reports [10]. A 2009 patient survey of 171 individuals found that up to 75% of statin users reported cognitive-related adverse drug reactions (ADRs) [47]. In many of these studies, the cognitive effects were anecdotal, with varying onset times and inconsistent responses upon re-challenge [19]. Evidence from a few clinical trials available at the time was inconclusive [13, 14, 48, 49]. For example, a small clinical trial (n = 209) found that 20 mg of lovastatin was linked to reductions in attention and psychomotor speed [14]. In contrast, a separate trial (n = 283) using 10 mg and 40 mg of simvastatin reported only minor cognitive declines, which were likely influenced by baseline differences in the cognitive tests [13]. Both studies were not only limited by their small sample sizes but also by their short follow-up period of just six months, making it difficult to draw long-term conclusions.

Since 2012, a limited number of studies have suggested that statin therapy may be associated with cognitive impairment. For example, a large (n = 480,000) retrospective cohort study in 2015 reported a strong association between first-time statin use and the onset of acute, reversible memory loss occurring within 30 days of initial exposure (hazard ratio [HR] 4.40; 95% confidence interval [CI]: 3.01–6.41) [12]. However, a 2015 meta-analysis of 25 RCTs found no link between statin therapy and cognitive impairment, challenging the FDA’s warning [50]. More recent meta-analyses have generally shown either a neutral or even positive impact of statins on cognitive function [51,52,53]. Although only a handful of recent studies have linked statins to harmful cognitive effects, some evidence of these negative effects still persists. A recent Mendelian randomization study published in 2022 concluded that statins negatively impacted cognitive performance, reaction time, and cortical surface area, though they did not affect biomarkers of AD progression or the risk of Lewy body dementia [11].

Evidence for Protective Effects of Statins on Cognition

Observational studies from the early 2000s suggested that statins might preserve cognitive function, though some reported little to no effect [54, 55]. In a United Kingdom case-control study, statins were associated with a more than 70% reduction in the relative risk of dementia [56]. Similarly, the Rotterdam Study linked both lipophilic and hydrophilic statins to a reduced risk of AD [57]. A nationwide survey in Taiwan found that statins, particularly the more potent types like atorvastatin and rosuvastatin, offered protective effects against dementia [39].

A meta-analysis found that each additional year of statin use reduced dementia risk by 20%, and every 5-mg increase in daily statin dosage lowered the risk by 11% [58]. Other studies have shown that long-term statin use is associated with a lower risk of AD, though short-term studies often report inconsistent effects [52, 59]. The follow-up duration appears to be crucial, as longer studies have demonstrated significant cognitive benefits compared to studies with shorter follow-up [59]. However, analysis of data from the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) and the Heart Protection Study (HPS) studies failed to demonstrate any cognitive protective effects of pravastatin or simvastatin [48, 49]. The Cache County and Cardiovascular Health Studies found no association between statin use and reduced dementia risk [55, 60]. Meta-analyses of observational studies have also yielded mixed results, with some showing no significant effect of statins on dementia or AD [16, 61].

For the purposes of this review, relevant observational studies and clinical trials from PubMed, Google Scholar, Embase, and Scopus were identified, focusing on the last five years but including classic studies and extending the timeline where literature was sparse (Table 2).

Table 2 Summary of recent studies examining the impact of statins on cognitive functionStatin Effects by Dementia TypeAlzheimer’s Disease (AD)

AD is the most common cause of dementia [66], primarily driven by the production and aggregation of Aβ and phosphorylated tau in the brain [44]. Aβ binds to cell membranes, leading to cell death in the brain [67]. Diet-induced hypercholesterolemia is linked to increased Aβ production and the progression of AD pathology [68]. Disturbances in brain lipid homeostasis can disrupt the blood-brain barrier, amyloid processing, endocytosis, myelination, signaling, energy metabolism, and increase inflammation. These lipid imbalances may contribute AD [69]. Furthermore, the APOE ϵ4 genotype, the most common genetic risk factor for AD, also plays a key role in lipid transport and metabolism [69]. Midlife hypercholesterolemia, compared to normal cholesterol levels, has been associated with a significantly higher risk of AD, with an estimated HR of 2.14 (95% CI 1.33–3.44) [6]. A retrospective study with nearly 12 years of follow-up found that statin use was linked to a reduced risk of AD, with HRs of 0.54 (95% CI: 0.32–0.91) for men and 0.53 (95% CI: 0.38–0.73) for women [18]. Similarly, a retrospective US-based Humana insurance claims study found that statin exposure was associated with a lower incidence of AD (RR 0.46; 95% CI, 0.44–0.49) [21]. A pooled analysis from a recent meta-analysis of 21 studies found that statin use was associated with a 32% lower risk of AD (odd ratio [OR] 0.68, 95% CI 0.56–0.81). This analysis also showed that both lipophilic and hydrophilic statins provided cognitive benefits. Moreover, high-potency statins were linked to a 20% reduction in AD risk, compared to a 16% reduction with low-potency statins [51]. The mechanisms linking statins to AD are not fully understood, but some studies suggest they may exert beneficial effects by slowing Aβ aggregation [45]. Nonetheless, the protective effect of statins on AD risk seems to be independent of their lipophilicity, although more studies are needed to confirm this [57]. In contrast, other studies have found no significant association between statin exposure, irrespective of their lipophilicity, and the risk of AD [