Statins’ Effects on Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) has brought about heavy economic and healthy burden worldwide. There is no effective therapy to prevent or delay the progression of AD. Statins are suggested as the alternative therapy for AD, although the positive effects of statins on AD are still full of controversy. Therefore, it is necessary to define sensitive AD population who would benefit from statin therapy and a preferable therapeutic regimen on statins to avoid detrimental effects on cognition. We summarized the pathogenesis of AD, especially those related to statins. With emerging clinical evidence, updated data on the correlation between statins and AD development are clarified in chronological order. We also retrieved the underlying mechanisms for beneficial and detrimental effects of statins on AD development. Then we discussed the factors that might affect the efficacy of statins from statin use (types, dosages, and therapy duration) to the sensitive population (sex, age, genetic factors, and comorbidities). Finally, we elaborated on the limitations of the current studies and the implications for the future research to guide the appropriate statin therapy in clinic.

1. Introduction

Alzheimer’s disease (AD) is a degenerative neurological disorder with high mortality and disability in the elderly. AD manifests cognitive decline in clinic and is characterized by cerebral deposition of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, abnormal neuronal metabolism, neuronal cell death, and subsequent brain atrophy. As the most common form of dementia, nearly 5.8 million Americans were living with AD in 2020, and the population will exceed 150 million in 2050 worldwide, bringing about heavy economic and healthy burden [1].

It is crucial to explore the pathogenesis and potential targets for AD. One epidemiological study early in 1998 reveals the correlation between AD and high levels of serum cholesterol [2], followed by inconsistent result [3, 4, 5]. After pooling data on 23,338 patients, a recent meta-analysis suggests that high risk of AD in relationship with hypercholesterolemia happens in midlife and early stages of aging [6]. Thus, cholesterol-lowering agent might have a potential role in AD management.

Statins, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor, that effectively lower blood cholesterol, are widely used as the first-line agent for hypercholesterolemia in the primary and secondary prevention of cardiovascular events. Most statins users are midlife or older adults with risk factors of cardiovascular and cerebrovascular diseases. Statins are reported to alter cognitive performance and AD development [7, 8, 9], although their positive role is still under debate [10, 11]. With more than 200 million people on statin therapy worldwide [1], it is critical to identify the role of statins on AD and explore the appropriate therapeutic plan for statins. Different from animal model studies, human studies produce inconsistent results. Some observational studies demonstrate that statins may prevent or delay the neurodegenerative process and reduce the risk of dementia or incident AD, especially in those who carry the APOE e4 allele or under 65 years old, while some other studies did not show any beneficial effects [12]. In fact, the mechanism involving statins in AD is complicated, including cerebral decomposition of Aβ and tau protein [13, 14], cerebral cholesterol balance [12, 15], neuroinflammation [14, 16], oxidative stress [13, 17], insufficient cerebral blood flow supply [18], abnormal blood-brain barrier [18], decreased neurotrophic factors [12, 19], and so on. Individual-related factors (including their genetic diversity, ethnicity, sex, age, and comorbidities) and statin-related factors (statin type, statin dose, and treatment duration) might alter the association between statin and cognition [12, 17]. Negative influence of statin on cognition might result from intracranial cholesterol depletion, reduced CoQ10, and decreased neurotrophic factor caused by statin therapy [12, 19].

Therefore, the identification of potential population who may benefit more from statin therapy and appropriate statin use might prevent or delay AD progress. We explored the pathogenesis of AD, especially those related to statins, and discussed the core position and related controversy of Aβ and tau protein. Then we reviewed the results of clinical research of statin therapy on AD, investigated underlying mechanisms for beneficial and detrimental effects of statins on cognitive performance, and analyzed potential factors modifying the cognitive effects of statins. Finally, we elaborated on the limitations of existing studies and the implications for future research to guide appropriate statin therapy.

2. Pathogenesis of AD

AD is a disease with complex pathogenesis, involving in gene and environmental factors. Amyloid-β (Aβ), tau protein, and neuroinflammation play leading roles in the development of AD [13].

2.1 The central position and challenges of Aβ and tau protein in AD

AD is characterized by cerebral accumulation of Aβ plaques, and tau neurofibrillary tangles. Aβ plaques are formed and deposited in different regions of the brain. These plaques are recognized as foreign material by the brain, which initiates an inflammatory and immune response by activating the microglia and releasing cytokines, eventually lead to neural cell death and neurodegeneration [20].

Aβ cascade theory was considered as the core of AD [21]. This theory holds that toxic Aβ fragments induce downstream damages: tau protein phosphorylation, neurofibrillary tangles, neuroinflammation, oxidative stress, neuron cell loss, and vascular damage, eventually leading to dementia. Besides Aβ, the over-phosphorylated tau protein also plays an important role, which affects the stability of the microtubule protein of the neuronal skeleton, leading to neurofibrillary tangle and destroying communication of neurons and synapses. More importantly, misfolding proteins of Aβ and tau can “infect” and spread to surrounding tissues like the prion virus [21, 22]. In fact, the core position of Aβ cascade theory has been challenged. Positron emission tomography (PET) tracking in the living brain shows that tau protein is present in the brain of normal elderly. Aβ appears to trigger the expansion of tau depositions from the hippocampal formation to the limbic system, and subsequently to the neocortex. Significantly, it is tau protein rather than Aβ accumulation is consistent with the pathological process of AD, which implies that Aβ might only play an enzyme-linked role, and tau protein promotes the pathological changes of AD [23]. Therefore, when Aβ activates the downstream pathogenic pathway, it might be ineffective to target on Aβ. Unfortunately, clinical trials target on tau protein also failed [13].

2.2 Hypercholesterolemia

In 1998, Notkola et al reported a positive relation between hyperlipidemia and increased risk of AD in a cohort study [3]. Later, Solomon et al reached a similar conclusion in a larger study, showing a positive association between serum cholesterol levels in midlife and AD risk following 21 years [4]. However, Mielke et al did not find any significant association between midlife serum cholesterol levels and risk of AD following 32 years [5]. To explain the discrepancy of these results, a meta-analysis was performed and showed that the highest risk for developing AD due to hypercholesterolemia mainly happens in midlife and early stages of aging, not in late life [6].

Unlike epidemiology reports, experimental studies provide strong evidence for hypercholesterolemia and the risk of AD [17]. Diet-induced hypercholesterolemia significantly enhances cerebral neuroinflammation, Aβ plaque deposition and cognitive impairment in Wistar rats [17].

Statins, as a cholesterol-lowering agent, is found to reduce the content of cholesterol and oxidative cholesterol in the brain, as well as the levels of total cholesterol, latosterol, and 24S-OH chol in cerebrospinal fluid in animal and clinical studies [15]. In AD animal models, statins attenuate the formation of β-amyloid, reduce the production of senile neurotic plaques and neurofibrillary tangles, and improve cognition [24, 25, 26, 27]. Simvastatin enhanced learning and memory performance in morris water maze test [28]. Lorenzoni et al made a similar observation in high-fat diet-feeding rats [29]. A meta-analysis of statin showed positive effects on cognitive function, especially in the younger mouse group [30]. Some observational studies make similar discoveries as animal studies, which demonstrated that statin treatment may prevent or delay the neurodegenerative process and reduce the risk of dementia or incident AD [8].

2.3 Cerebral vascular abnormality

Cerebral vascular alterations are discovered in over half of AD patients [18]. Patients with AD exhibit substantial atherosclerosis in leptomeningeal arteries and the circle of Willis [18]. In the late stage of AD, microvascular thinning and collapse are exhibited in up to 90% of the patients. Cerebral amyloid angiopathy (CAA) occurs in 85–95% of AD, where Aβ deposits in the outer membrane, middle membrane, and capillary basement membrane of intracranial arteries, leading to vascular wall damaging, causing micro infarction and micro hemorrhage, eventually cognitive decline [18].

Blood flow and metabolism decrease are discovered in cognitive-related brain areas (parietal, temporal, frontal lobes, especially and hippocampus) in AD patients through single-photon emission computed tomography (SPECT) perfusion imaging and fluorodeoxyglucose PET imaging test. Even in the pre-clinical stage of AD, similar findings are discovered in cognitive-related brain areas (hippocampus, entorhinal cortex, amygdala, and anterior cingulate gyrus) [18]. Therefore, the roles of cerebral vascular abnormalities in AD pathogenesis might be underestimated.

2.4 Inflammation, oxidative stress, and other mechanisms

Neuropathology in human and animal studies confirmed that inflammation, oxidative stress, and immune regulation are involved in the pathogenesis of AD. Aβ deposits activate chronic inflammation and oxidative stress, which lead to the damage of neurons and dendrites and hinder intraneuronal communication [13, 20]. An abnormal gut microbiome causes systemic inflammation and neuroinflammation and is involved in AD progression via the brain-gut metabolic axis. Additionally, dysbiosis of the gut microbiome increased cytotoxic bile acid, which can cross the brain-blood barrier and deposit in the brain, leading to neuron apoptosis and neurodegeneration [17]. Synaptic dysfunction and neurotransmitter imbalance also participate in AD progression [20].

3. Clinical research of statins on AD

Epidemiologic studies suggest a close relationship between plasma hypercholesterolemia and AD risk [4, 6]. High serum cholesterol levels may alter sterol balance across the central nervous system [12]. Statins are wildly used in preventing and treating hypercholesterolemia, cardiovascular, and cerebrovascular diseases. Vasoprotective and neuroprotective effects are discovered in statin therapy in some studies [8, 10, 18, 31]. Therefore, the use of statins to reduce the risk of dementia and AD becomes a hot topic widely.

In 2000, Jick et al tried to explore whether modifying lipid burdens or components could lower the risk of developing dementia by using an observational approach. The results showed that individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia but cannot distinguish between AD and other forms of dementia [10]. After these findings, interest has arisen in the potential for statins to delay cognitive decline or dementia in people with older age.

In 2006, a meta-analysis of statins for the prevention and treatment of dementia searched and sifted seven independent data sets from the literature over the last 40 years. They demonstrated that statins use did not show a beneficial effect on the risk of dementia or AD [11].

In 2013, Wong et al. conducted a meta-analysis of 15 observational studies of statins on dementia and AD. They observed a slight protective effect of statins in the prevention of AD and all-type dementia independently of the lipophilicity of the statins [8].

In 2013, Song et al. carried out another meta-analysis of eight prospective cohort studies including AD, vascular dementia and other dementia to examine the association of statins use with risk of dementia, which showed a significant association between statins use and a reduced risk of dementia, but no enough evidence for statins to delay the progression of AD [9].

In 2015, a review by McGuinness et al., including two double-blind, randomized, and placebo-controlled trials (HPS 2002 and PROSPER 2002), assessed the evidence of statins for the prevention of dementia. In these trials, simvastatin or pravastatin were administered for at least 12 months to 26,340 people at risk of dementia. Both studies were at low risk of bias. Researchers discovered that initiating statin therapy in late life to people at risk of vascular disease do not prevent cognitive decline or dementia [32].

In 2018, Chu et al. conducted a systematic review and meta-analysis of 25 cohort studies published before 2017, and found that statins use significantly reduced the risk of developing all-cause dementia, AD, and MCI, but not incident VaD. Furthermore, statins may offer stronger preventative benefits for neurodegenerative dementia (such as AD) and MCI. Subgroup analyses suggested that both hydrophilic and lipophilic statins showed beneficial effects in preventing all-cause dementia and AD [33].

In 2020,Poly et al. performed a meta-analysis of 30 relevant observational studies from 2000 to 2018, including 9,162,509 participants (84,101 dementia patients). After fully adjusted in age, gender, and different types of covariates, statin use was discovered to be associated with a 17% decreased risk of all-cause dementia, and a 31% decreased risk of AD. North American individuals had a lower risk of dementia compared with Europeans and Asians [31].

Also in 2020, Xuan et al. conducted another meta-analysis including nine randomized controlled trials, to evaluate the efficacy of statins on AD. They discovered that statin therapy improved the scores of the MMSE scale in the short term (≤12 months) but was not obvious after a longer time, and improved activities of daily living and the neuropsychiatric status, but not ADAS-Cog scale scores in AD patients. Statins appeared more effective in patients with high cholesterol levels and APOEε4 gene carriers [7].

Taken together, based on current evidence, statins seem to be correlated with a beneficial effect on AD patients, especially in those with high cholesterol levels and APOEε4 gene carriers, which requires future large RCT tests to validate.

4. Potential mechanism of statins on AD development

Statins may improve AD development by reducing intracranial Aβ and phosphorylated tau, improving cerebral blood flow and blood-brain barrier, decreasing inflammation and oxidative stress, and other mechanisms. The harmful effect of statins on cognition might be mainly attributed to excessive inhibition of intracranial cholesterol synthesis, which interferes with the formation of the neuronal cell membrane and myelin sheath, and impair synaptic function [34].

4.1 Statins reduce intracranial Aβ, phosphorylated tau

Statins regulate the activity of amyloid precursor protein (APP) related processing enzymes, decrease Aβ production and accumulation, and promote Aβ clearance, thus reducing intracranial Aβ levels [35, 36, 37], by MAPK/Erk1/2 [38], Rho/ROCK [39], or AKT/GSK3β signaling pathway [27].

Adult male guinea pigs fed with high doses of simvastatin for 3 weeks, showed a reduction of Aβ content in both brain tissue and cerebrospinal fluid, and the beneficial effects were reversed upon discontinuation of the drug [40]. AD mice model fed with atorvastatin and pitavastatin not only showed a reduction in intracranial Aβ and phosphorylated tau but also an improvement in cognitive function [26]. Cellular experiments by Yamamoto et al. showed that simvastatin and atorvastatin induced extracellular Aβ degradation by increasing neprilysin secretion from astrocytes through activation of MAPK/Erk1/2 pathways [38].

Statins reduce phosphorylated tau protein deposition. Boimel et al. demonstrated that either simvastatin or atorvastatin attenuated neurofibrillary tangles (NFTs) and improved memory in a transgenic mouse model of tauopathy. In addition, both lipophilic (simvastatin) and hydrophilic statin(atorvastatin) attenuated NFTs, suggesting that the ability of statins to cross the blood-brain barrier might not influence their effects on cognition [25]. Van der Kant et al. conducted a drug screening trial using neuronal cells generated by induced differentiation of pluripotent stem cells (iPSC) and found that statins (atorvastatin, simvastatin, fluvastatin, and rosuvastatin) reduced both Aβ secretion and phosphorylated tau protein deposition. However, they found that atorvastatin and simvastatin were toxic to astrocytes even at low concentrations, which needs to be confirmed by further studies [41].

4.2 Potential protection on cerebral blood flow, blood-brain barrier

Atorvastatin and pitavastatin can improve the blood-brain barrier by inhibiting the activation of MMP-9 and inflammatory reaction, thus attenuating neurovascular unit destruction in APP transgenic mouse models [42]. Tong et al. discovered that simvastatin improved cerebrovascular reactivity and counters soluble amyloid-beta, inflammation, and oxidative stress in aged APP mice [27]. One small sample-sized clinical study demonstrated that 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen, and insular cortices in persons at risk for AD [43], which should be validated by a large sample of clinical trials.

4.3 Anti-inflammatory and antioxidant effects

The anti-inflammatory and antioxidant effects of statins on AD have been confirmed in animal experiments [17, 27, 44, 45]. A great number of studies have shown that statins exert an anti-inflammatory and antioxidant effect through the activation of microglia and AGEs/NADPH oxidase/NF-kB signal pathway and thus, relieving neurodegeneration, and improving cognitive function [45, 46]. Statins not only reduce the pro-inflammatory mediators: the tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), prostaglandin E2 (PGE2), interleukin-6 (IL-6), interferon-gamma (IFN-γ), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), and reactive nitrogen species (RNS) but induce the anti-inflammatory mediators such as interleukin 10 (IL-10) [12]. Simvastatin reduced Aβ-induced inflammation and oxidative stress [44]. Atorvastatin improved cognitive impairment by inhibiting inflammatory responses, suppressing Aβ-induced oxidative stress, and protecting mitochondrial function in hippocampal neurons [47, 48]. However, there are no clinical data on the effect of statins on cerebral inflammation and oxidation in AD patients.

4.4 Other mechanisms

Wnt/β-catenin signaling pathway is involved in the differentiation and maturation of dentate gyrus granulosa cells, dendritic branching, depolarization and formation, synaptic stability, and plasticity. Tong et al. showed that simvastatin activated Wnt/β-catenin pathway, subsequently rescuing memory and granule cell maturation in an AD mouse model [49].

Statins might affect memory performance by modulating the transcriptional activity of neurotrophic factors and related receptors. Simvastatin has been suggested to enhance CREB (cAMP Response Element-Binding protein) and BDNF (Brain-Derived Neurotrophic Factor) in mice hippocampus, consequently improving memory functions [50, 51].

4.5 Harmful effect of statins on cognition

Some studies have shown the dementrial effect of statins on cognition. Hamano et al found that high doses of pitavastatin caused tau aggregation and even neuron apoptosis [39]. Treatment of elderly beagle dogs with human physiological doses of atorvastatin did not improve cognitive deficits and even resulted in transient reversible learning dysfunction [52]. Long-term combined use of simvastatin and four medications commonly prescribed to the Swedish elderly were found to impair explorative behavior and reduce synaptic functions in young adult mice [53].

The underlying mechanisms for statins-induced cognitive dysfunction may be mainly due to excessive inhibition of intracranial cholesterol synthesis, which leads to the depletion of intracranial cholesterol, thus interfering with the formation of the neuronal cell membrane and myelin sheath, and causing synaptic loss [12]. Furthermore, statins might induce oxidative stress and neuronal injury by reducing cerebral CoQ10 or BDNF levels [19]. The lower serotonin activity induced by statin might bring about behavior change that negatively influences cognitive performance [12].

5. Factors affecting the efficacy of statins

Statins therapy influences AD development through cholesterol-dependent or independent effects. Individual-related factors (age, sex, and genetic factors), statin-related factors (type, dosage, and duration), and comorbidities interfere with statins’ effect on cognition.

5.1 Type, dosage, and treatment duration of statin

Whether lipophilic statins influence greater on AD progression more than hydrophilic statins is still inclusive. One meta-analysis reported that lipophilic statins were associated with a lower risk of AD [31]. On the contrary, one systematic review indicated that hydrophilic statins had more protective effects in preventing all-cause dementia and possibly AD in comparison to lipophilic statins [33].

Statins have a dose-dependent role in the prevention of cardiovascular and cerebrovascular events, but whether statins have a similar dose-dependent relationship in the prevention of dementia is still unclear. Tong et al. found that higher doses of simvastatin treatment improved both short-term and long-term memory in young adult AD mice, while a normal dose of simvastatin treatment (20 mg/kg/day for 8 weeks or 40 mg/kg/day for 3–6 months) failed to reverse intracranial Aβ deposition in AD mice [44, 54]. Wang S et al. found that high-dose (10 mg/kg/day) and long course of atorvastatin therapy prevented Aβ-induced neuroinflammatory responses, and improve impaired cognitive function; whereas the low-dose (5 mg/kg/day) atorvastatin did not show beneficial effects [55]. One meta-analysis showed that a 5-mg increase in the daily dose of statins resulted in an 11% decrease in dementia risk [56]. However, another two studies did not find any dose-dependent evidence between statins and dementia [57, 58].

Basic and clinical studies have found that only large or super doses of statins decrease intracranial cholesterol. Animal experiments showed that super doses of statins, such as lovastatin (100 mg/kg/day), pravastatin (100 mg/kg/day or 300 mg/day), and simvastatin (50 mg/kg/day), which is far above the clinical dosage, reduced the total amount of intracranial cholesterol and 24S-OH. In the clinical study, a high dose of statin (simvastatin 80 mg/day), rather than a regular dose of simvastatin (20 mg/day), decrease total cholesterol, lathosterol, and 24S-OH in cerebrospinal fluid [15]. Notably, intracranial cholesterol exhaustion induced by excessive lipid-lowering effect might lead to cognitive impairment [50]. So, it is possible to ensure a positive influence on cognition only when appropriately reducing cerebral cholesterol while maintaining cerebral cholesterol homeostasis.

As for treatment duration, a meta-analysis of rodent AD models found that a longer duration of statins(>6 months) got more benefit on Aβ deposition [24]. For patients at high risk of vascular dementia, more than 1 year of statin therapy significantly reduced the risk of dementia compared with nonusers [59]. However, one study with a follow-up of 10–37 years failed to show any associations between long-term statins exposure and cerebral amyloid or tau burden [60]. Since this research did not track cognition function, circulating lipid levels, and dose of statin, the result should be evaluated by further studies.

5.2 Age and sex

Aging is a major important risk factor for memory decline and AD. A study from the British Biological Sample Bank demonstrates that statin therapy favored individuals under 65 years old in cognitive function [61]. Volloch et al. recommended initiating statin therapy in the pre-clinical stage of AD [62]. The impact of sex in the effect of statins on AD and cognitive performance is still inconclusive, although a low level of estrogen in females serves as the main risk factor for AD [12]. Thus, future studies are required to decipher the statin cognitive effect concerning aging and sex.

5.3 Genetic factors

The apolipoprotein E ε4 allele (APOEε4) is the strongest genetic risk factor for AD. One longitudinal study of over 6 years has found that statin seems to attenuate memory decline in participants with heart disease and APOEε4 carriage [63]. Nevertheless, one autopsy-based research did not demonstrate any effect of APOE4 on AD pathological biomarkers in the statins exposure population [64], which needs to be carefully evaluated since the dosage and course of statin were not taken into account.

5.4 Comorbidities and renin-angiotensin system (RAS) system

Hypertension, ischemic heart disease, and stroke are high-risk factors for dementia. Those comorbidities might interfere with the outcome evaluation of statins research [12]. It is worth noting that neuroinflammation induced by chronic activation of the RAS system plays a role in the pathogenesis of AD. A recent meta-analysis including over 3 million individuals showed a reduced risk of dementia in subjects taking ARBs agents, which reduced the risk of any dementia by 22% as compared to other antihypertensive medication, especially in AD (27% reduction in risk) [65]. Barthold et al made further research and found the combination of ACEI or ARB agent and statin decreases AD risk [66].

6. Conclusion

With the aging of the population, age-related diseases have become the main killer threatening lives, including dementia, cardiovascular, and cerebrovascular disease. The main causes of mortality in AD patients are cardiovascular diseases and cerebrovascular diseases, similar to the general population [67]. So, the prevention of cardiovascular and cerebrovascular events should be put in the same position as a reversal of AD progress in AD patients. Statin, as the first-line agent to prevent cardiovascular and cerebrovascular events for the elderly, has been reported to potentially delay AD development, thus receiving extensive attention.

We summarized the current evidence of statin therapy on AD and provided the following suggestions. Firstly, great efforts are required to avoid the adverse effects of statins on cognition and identify suitable populations who may benefit from a statin. Secondly, patients with middle-aged or APOE4 carriers might benefit from statins, and women aged 65–75 years old should not be recommended to use simvastatin [68]. Thirdly, due to the limited evidence on brain cholesterol and cognition, it is unclear whether there is a safety threshold value for brain cholesterol in statin therapy. Finally, the combination of statins and other agents needs to be confirmed in future studies.

In conclusion, the positive evidence of statin’s effects on AD have not been fully confirmed. Stratified studies revealed some potential factors, improving or deteriorating statin effect on cognition. Future studies are required to provide more evidence for the rational use of statins and define sensitive populations.

Acknowledgments

This project was supported by Guangzhou Science and Technology Program (202201020343), Guangdong Province, China.

Conflict of interest

The author declares that there are no conflicts of interest.