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Effects of Plasma Lipids and Statins on Cognitive Function

Objective: Dementia is the fourth most common cause of death in developed countries. The relationship between plasma lipids and cognitive function is complex and controversial. Due to the increasing life expectancy of the population, there is an urgent need to control vascular risk factors and to identify therapies to prevent and treat both cognitive impairment and dementia. Here, we reviewed the effects of plasma lipids and statins on cognitive function. Data Sources: We searched the PubMed database for research articles published through November 2017 with key words including “plasma lipids,” “hyperlipidemia,” “hypercholesterolemia,” “statins,” and “cognition function.” Study Selection: Articles were retrieved and reviewed to analyze the effects of plasma lipids and statins on cognitive function and the mechanisms underlying these effects. Results: Many studies have examined the relationship between plasma lipids and cognitive function, but no definitive conclusions can be drawn. The mechanisms involved may include blood-brain barrier injury, the influence on small blood vessels in the brain, the influence on amyloid deposition, and a neuroprotective effect. To date, most studies of statins and cognition have been observational, with few randomized controlled trials. Therefore, firm conclusions regarding whether mid- or long-term statin use affects cognition function and dementia remain elusive. However, increasing concern exists that statins may be a causative factor for cognitive problems. These adverse effects appear to be rare and likely represent a yet-to-be-defined vulnerability in susceptible individuals. Conclusions: The association between plasma lipids and cognition, the mechanism of the influence of plasma lipids on cognitive function, and the association between statins and cognitive function are complex issues and currently not fully understood. Future research aimed at identifying the mechanisms that underlie the effects of plasma lipids and statins on cognition will not only provide important insight into the causes and interdependencies of cognitive impairment and dementia, but also inspire novel strategies for treating and preventing these cognitive disorders.

approximately one-third of AD cases are due to modifiable vascular risk factors [5] because of their potential impact on the neurovascular unit. [6] Due to the increasing life expectancy of the population, there is an urgent need to control vascular risk factors and to identify therapies to prevent and treat both cognitive impairment and dementia. Here, we reviewed the association between plasma lipids and cognition function and the underlying mechanisms.

PlasMa lIPIds and cognItIve functIon
In the Finnish study titled Cardiovascular Risk Factors Aging and Dementia, midlife measures of total cholesterol were significant predictors of cognitive impairment. Moreover, it was shown that a high midlife cholesterol level increased the risk for VaD. [7] Some studies have reported that higher levels of late-life cholesterol were associated with a higher risk of VaD. In contrast, a longitudinal study of 1159 elderly Chinese individuals found associations between the elevated levels of total cholesterol and low-density lipoprotein (LDL) and the accelerated cognitive decline. [8] The literatures generally suggest that the risk of mild cognitive impairment (MCI) and dementia is associated with hypertriglyceridemia, high LDL levels, and low high-density lipoprotein (HDL) levels. [9,10] A large cohort study (n = 7087) showed that a high triglyceride level was the only component of metabolic syndrome that was significantly associated with the incidence of VaD (hazard ratio [HR]: 2.27); no such association was found for AD (HR: 0.90). [11] Hypertriglyceridemia-induced/associated atherosclerosis might contribute to cognitive decline in patients with type 2 diabetes. [12] Panza et al. [13] noted that hypertriglyceridemia was associated with increased risk of dementia syndromes, particularly VaD. An elevated LDL level is particularly atherogenic and may be closely related to VaD. [14] A Swedish study (n = 60) found that higher apolipoprotein B (ApoB) levels at baseline predicted dementia at least 3 years later, although all forms of dementia were included in this small study. [15] One study also indicated that the ApoB/LDL ratio might be a potential clinical index for vascular cognitive impairment. [16] Most cross-sectional studies that included participants aged over 75 years showed an association between increased HDL cholesterol (HDL-C) levels and better performance on cognitive tests. [17] In addition, a prospective study has confirmed the association of lower ApoA-I levels with increased dementia risk. [18] A higher ApoB/ApoA-I ratio increased the risk of cognitive decline over 2 years in cognitively normal individuals. [19] Therefore, an elevated ApoA-I level and a decreased ApoB/ApoA-I ratio might be associated with decreased dementia risk.
In contrast, one study found that higher levels of late-life cholesterol were associated with a lower risk for VaD. [20] Other large studies of older adults have found an association of high triglyceride [21] and LDL levels with better cognitive performance. [22] Furthermore, in a recent longitudinal study of 192 adults with AD, rising LDL levels were associated with a trend toward improvement in functional performance. [23] Recently, one study reported that high total serum cholesterol in late life was not associated with MCI, AD, VaD, any form of dementia, or cognitive decline. [24] Vicario et al. [25] reported that only dyslipidemia was unrelated to cognitive impairment in the Cardiovascular Prevention Program (n = 1365). The latest research showed that late-life measurements of HDL-C and triglycerides were not associated with increased risk of VaD, and HDL-C was not associated with the risk of MCI, AD, or any form of dementia. [24] A pooled analysis of two Finnish prospective population-based cohort studies (n = 13,275) found that the baseline ApoB level was not associated with incident AD or dementia 10 years later. [26] The relationship between plasma lipids and cognition is very complex and controversial. As with blood pressure, inconsistencies might reflect the timing of cholesterol measurements according to age, with older people possibly being less likely to receive lipid-lowering therapy (an example of the so-called "generational effect") and differences in the clinical onset of dementia.

Blood-brain barrier injury
Brain cholesterol is involved in synapse development, synapse formation, dendrite differentiation, axonal elongation, and long-term potentiation. [27] In the adult brain, the synthesis of primary cholesterol occurs in astrocytes and to a lesser extent in neurons. [28] Cholesterol is transported within the brain by local lipoproteins. Brain cholesterol metabolism is unrelated to metabolism in peripheral tissues and the central nervous system (CNS), and plasma cholesterol/lipoprotein compartments are strictly segregated by the blood-brain barrier (BBB).
The BBB is created by the tight junctions between the endothelial cells of brain microvascular tissue and the astrocyte foot processes surrounding capillary endothelial cells. [29] BBB injury has been recognized as a contributory factor to the development and progression of cognitive impairment. Recently, multiple studies have reported that rats fed with high energy diets, specifically diet rich in saturated fats and cholesterol, exhibited increased BBB permeability along with cognitive dysfunction. [30][31][32] Although normal aging increases BBB permeability, [33] oxidized LDL (oxLDL) promotes endothelial cell activation including increased the adhesion of monocyte to the vascular wall and the induction of the nuclear factor-κB pathway. A recent study showed that the activation of microvascular endothelial cells by LDL increased the secretion of the inflammatory mediators such as tumor necrosis factor alpha and interleukin-6 and decreased the membrane localization of the tight junction protein ZO-1. [28] LDL isolated from patients with hypercholesterolemia was more oxidized and inflammatory in endothelial cells than that isolated from healthy age-matched participants. [28] In conjunction with these studies, another investigation demonstrated that anti-inflammatory and lipid-lowering agents could reverse the high fat-induced BBB damage in rats. [30] The reversal of BBB damage would, therefore, be expected to be accompanied by improvement in cognitive function. Inflammation and lipid oxidation might play an important role in the development of VaD.
HDL-C might be involved in the removal of excess cholesterol from the brain mediated by ApoE and heparin sulfate proteoglycans in the subendothelial space of cerebral microvessels. In addition, HDL particles reverse the inhibitory effect of oxLDL particles on endothelium-dependent arterial relaxation and inhibit cytokine-induced expression of endothelial cell adhesion molecules. [34] Paraoxonase 1 is an A-esterase with peroxidase-like activity present on the surface of HDL that decreases the peroxidation of LDL. [35] These might be related to the protective effect of HDL against cognitive decline.

Influence on small blood vessels in the brain
Although several studies have reported no association between LDL cholesterol (LDL-C) and magnetic resonance imaging markers of cerebral small vessel disease, [36,37] one cohort study (n = 1919) revealed a significant relationship among increased HDL-C, decreased LDL-C, and white matter hyperintensity (WMH) progression. [38] Furthermore, in 1135 acute ischemic stroke patients, hypercholesterolemia, hypertriglyceridemia, or the use of lipid-lowering medication was associated with a decreased severity of WMH. [39] Unfortunately, the authors were unable to assess the contribution of statin therapy to the observed association, which might have confounded their findings. Although a smaller cohort study (n = 112) showed no association between midlife total cholesterol and WMH two decades later, lipid-lowering therapy reduced the risk of WMH in later life. [40] And low HDL levels increased the severity of white matter changes. [41] Influence on the deposition of amyloid Some evidences indicate that changes in brain cholesterol homeostasis are associated with the main pathological features of AD, especially amyloid beta (Aβ). Evidences also suggest that amyloidogenic amyloid precursor protein (APP) processing might preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts and that alterations in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Functional cell biology studies further support the critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase, resulting in altered Aβ production. Decreased cholesterol levels have been shown to inhibit β-secretase activity while increasing the activity of α-secretase, the major proteolytic enzyme involved in APP metabolism. [42] Experimental studies suggested that high cholesterol accelerated the production of Aβ, the putative pathologic species in AD, by shifting APP metabolism from α to β cleavage products. [43] Animal studies showed that intervention with a high cholesterol diet led to memory deficits, increased oxidative stress, and doubled the concentration of amyloid in the hippocampus. [44] One study demonstrated that LDL from AD and AD with VaD patients was more damaging to endothelial barrier properties and increased release of inflammatory cytokines. [28] However, HDL-C could prevent aggregation and polymerization of Aβ, thus slowing or even preventing the development of AD. [39,40] HDL-C was also reported to have anti-inflammatory properties. [42] ApoE is an important protein involved in cerebral cholesterol transport and influences aggregation and clearance of Aβ peptide. The ApoE ε4 allele in both homozygosis and heterozygosis increases the risk of developing AD. [45] The ε4 allele is associated with a higher risk of atherosclerosis and higher plasma levels of total cholesterol and LDL-C. [34] In addition, several other genes involved in cholesterol metabolism have been reported to be associated with AD including adenosine triphosphate-binding cassette subfamily A member 7, [46] clusterin, and sortilin-related receptor (SORL1). [34] Neuroprotective effect In addition, in vitro studies have shown that cholesterol acts as an antioxidant and therefore plays a protective role in dementia pathogenesis, possibly through intercepting prooxidants to create oxysterols, which are less toxic than free radicals. [20] High cholesterol might have a protective effect by increasing gamma-glutamyltransferase. This enzyme plays an important role in amino acid uptake and transport and could reduce the neurotoxic effects of amino acids. [47] statIns and cognItIve functIon Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the rate-limiting enzyme in the cascade of cellular cholesterol biosynthesis. Statins thereby reduce the formation and entry of LDL-C into the circulation and upregulate LDL receptor activity, lowering LDL-C and triglycerides and increasing HDL-C. At present, firm conclusions regarding whether midor long-term statin use might influence cognitive decline and dementia remain elusive. [48] Statins have neuroprotective effects through a variety of mechanisms. At the same time, the cognitive problems caused by statins should not be overlooked.
To date, most studies on statins and cognition are observational, and few randomized controlled trials (RCTs) have been conducted. Two large, double-blind, placebo-controlled RCTs of statins, the Heart Protection Study (HPS), [49] and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, have been conducted. [50,51] In the HPS, simvastatin had no effect on cognitive decline, compared to the control. [49] In the PROSPER trial, pravastatin treatment was not associated with a change in cognitive test results. [50,51] Several observational studies (conducted almost exclusively in adults aged >65 years) have considered the association between statin use at the baseline study visit and subsequent cognitive decline or incident dementia. Likewise, no association was observed between baseline statin (irrespective of their lipophilicity) use and incident dementia in the Three-City study, in which the follow-up period was 7 years. [52] However, the Gingko Evaluation of Memory Study showed that time-updated statin use was associated with a reduced risk of dementia in participants without MCI at baseline. [53] New statin use during follow-up was reported to be associated with a reduced risk of incident dementia. [54] Trials of statins assessing outcomes relevant to cognition and dementia are rare. Several observational studies have observed an association between statin use and dementia. These have been systematically reviewed by several groups of authors. All reviews found significant heterogeneity between studies and reported the biases and confounding factors commonly associated with observational research, making conclusive results and implications for practice difficult to establish and disseminate. [55][56][57] Many previous studies have demonstrated the beneficial effects of statins on endothelial dysfunction and chronic inflammation. [58] However, statins might also confer neuroprotection by other mechanisms. For example, statins, particularly lipophilic statins, might cross the BBB and exert antioxidant and anti-inflammatory effects within the CNS or modulate cholesterol metabolism in the brain. [59,60] Experiments in animal and cell models of AD have also suggested that statins modulate Aβ; however, few evidences currently support a similar effect in humans. [61] In addition, statins might modulate brain tau metabolism. [61,62] However, increasing concern exists that statins may be a causative factor of cognitive problems. Randomized trials, case reports, observational studies, and postmarketing surveillance have all reported data regarding cognitive impairment in people using statins. [53,63,64] Symptoms of confusion, forgetfulness, and memory loss have been reported within a few days after therapy, while other reports described symptom onset years after commencing statin use. Overall, the symptoms were not serious and reversed within a few weeks of ceasing statin therapy. Subsequently, at least three groups have systematically evaluated the situation and found no significant evidence showing that statins cause cognitive impairment. [65][66][67] The consistency of the independent findings of all recent reviews further shows that, to date, the evidence does not indicate an adverse effect of statins on cognitive function. Furthermore, these adverse effects seem to be rare and likely represent some yet-to-be-defined vulnerability in susceptible individuals. [68] conclusIons The associations between plasma lipids and cognition and the underlying mechanism, and the relationship between statins and cognitive function are complex and currently not fully understood. Given the aging population, there is an urgent need to identify treatments to prevent and treat cognitive impairment and dementia. Statins have important benefits in patients with or at high risk of cardiovascular and/or cerebrovascular events that far outweigh the putative risks of cognitive dysfunction as an adverse effect. The true incidence of these adverse effects cannot be determined with currently available data. Nevertheless, because of the potentially serious nature of cognitive dysfunction, the widespread use of statins, and the high prevalence of cognitive impairment resulting from any causes (particularly aging and concomitant cardiovascular and cerebrovascular diseases), patient reports regarding cognition should be taken seriously and be appropriately evaluated. Future research aimed at identifying the mechanisms that underlie plasma lipid and statin effects on cognition will not only provide important insights into the causes and interdependencies of cognitive impairment and dementia but also inspire novel strategies for treating and preventing these cognitive disorders.

Conflicts of interest
There are no conflicts of interest.