Cholesterol and Alzheimer's disease

A possible role for cholesterol in AD was based on observations of AD neuropathology among relatively young individuals with no history of dementia but with coronary heart disease (Sparks 1990). A central event in the development of AD is thought to be the abnormal processing of the cell membrane‐associated amyloid precursor protein (APP) followed by deposition of toxic β‐amyloid (Aβ) protein in the form of amyloid plaques in the extracellular space of the neocortex (Selkoe 2001). APP is a protein containing 770 amino acids. Aβ peptide is generated by the sequential cleavage of APP by beta and gamma secretase in the amyloidogenic pathway. Aβ genesis may be precluded if APP is instead cleaved first by alpha secretase within the Aβ domain, and then by gamma secretase, forming a non‐amyloidogenic fragment (Cole 2007). The non‐amyloidogenic pathway appears to be neuroprotective compared to the neurodegenerative, amyloidogenic pathway (Vetrivel 2006). Aβ occurs in two different forms, Aβ40 and Aβ42, varying in the length at the C terminus. It is the longer Aβ42 that aggregates more avidly. Early work discovered that elevated cholesterol levels led to greatly reduced levels of non‐amyloidogenic APP alpha in vitro (Bodovitz 1996). Perhaps more importantly, subsequent studies suggested that cerebral Aβ generation in vitro (Mizuno 1999; Simons 1998), and in vivo (Burns 2003; Refolo 2000; Sparks 1994), is cholesterol dependent. Cell biology investigations indicated that specialised cellular membrane microdomains rich in cholesterol and sphingolipids, termed lipid rafts, might be the link between cholesterol and amyloidogenic processing of APP. Both beta and gamma secretases are active in lipid rafts and it appears that APP processing within these lipid rafts by secretases determines the levels of Aβ production (Ehehalt 2003; Vetrivel 2004).

The ApoE ϵ4 allele is associated with sporadic AD. Meta‐analysis has shown that the ApoE ϵ4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes (Farrer 1997). It acts mainly by modifying age of onset, with each copy of the allele lowering the age at onset by almost 10 years (Corder 1993). This is significant in the context of cholesterol metabolism as ApoE acts as a cholesterol transporter in the brain. It binds directly to the Aβ peptide and influences its fibrillogenesis and clearance in vitro (Strittmatter 1993), and in vivo (Naslund 1995; Wisniewski 1995). ApoE is critically important for the formation of fibrillar Aβ in brain parenchyma in vivo (Holtzman 2000). Two genome‐wide association studies reported a significant association of AD with a locus within the clusterin (CLU) gene (Harold 2009; Lambert 2009). Functionally, clusterin has similarities to ApoE as both are major brain apolipoproteins and act as cholesterol transporters in the central nervous system. Both are also present in amyloid plaques and interact with Aβ, and regulating the conversion of Aβ into insoluble forms, co‐operating to suppress Aβ deposition and modifying Aβ clearance at the blood‐brain barrier (BBB) (van Es 2009). The amyloid cascade hypothesis states that an imbalance between production of and clearance of Aβ in the brain is the initiating event in the pathogenesis of AD, ultimately leading to neuronal degeneration and dementia (Hardy 2002), and thus theoretically links cholesterol metabolism to the development of AD.

There is also emerging evidence that genetics may play a role in responsiveness to statins. See Sabbagh 2012 for a review of findings in which new polymorphisms have been discovered that influence statin responsiveness. These have not been explored in AD and may aid in a priori identifying those most likely to benefit from treatment.

Central and peripheral cholesterol pools are separate, however, and almost all cholesterol in the brain is synthesised locally and is not transferred into plasma because of the BBB (Dietschy 2001). How serum cholesterol affects brain cholesterol has been a major question to date. Brain cholesterol content does not seem to be affected by high serum low‐density lipoprotein cholesterol (LDL‐C) or low serum high‐density lipoprotein cholesterol (HDL‐C) levels, perhaps as a result of the stability of cholesterol in myelin; however, it has not been established whether intramembranous lipid domains or intracellular cholesterol content are affected (Lane 2005). Studies in animal models have shown that diet‐induced hypercholesterolaemia increases Aβ and ApoE concentrations in the temporal and frontal cortices, but not in the cerebellum, and that these regional increases parallel the amyloid pathology observed in the AD brain (Wu 2003). Side chain‐oxidised cholesterol metabolites, such as hydroxy‐cholesterols, do cross the BBB. In the steady state in the adult brain, cholesterol clearance is facilitated by the formation and excretion of 24‐hydroxycholesterol (Lutjohann 2000). This is the major pathway for efflux of brain cholesterol and is crucial for maintenance of brain cholesterol homeostasis (Reiss 2004). 27‐Hydroxycholesterol is also found in the brain and may also provide a link between hypercholesterolaemia and AD (Heverin 2005); the contribution of the 27‐hydroxylase pathway to AD is an area in need of further exploration.

Several epidemiological studies have shown an association between high serum cholesterol levels and an increased susceptibility to AD (Jarvik 1995; Kivipelto 2002; Notkola 1998). The Notkola study was a long‐term prospective study that found elevated total serum cholesterol level was a risk factor for AD, independent of the ApoE ϵ4 allele; however, the association between AD and the ApoE ϵ4 allele became weaker after adjustment for serum total cholesterol (Notkola 1998). The authors concluded that some of the effect of the ApoE ϵ4 allele on the risk of AD might be mediated through elevated levels of total serum cholesterol. The Kivipelto study was again a prospective population‐based study that showed elevated mid‐life total cholesterol level was a risk factor for AD and was independent from risk from the ApoE ϵ4 allele and high mid‐life systolic blood pressure (Kivipelto 2002). The Jarvik study was a case‐control study, which again showed a positive association between serum cholesterol and risk of AD (Jarvik 1995). More recently, the Norwegian Counties Study, a long‐term observational study, showed dementia death was associated with increased total cholesterol levels in mid‐life (Strand 2013).

There may also be converging pathogenic mechanisms between cerebrovascular and Aβ plaque pathology ‐ cerebrovascular pathology with ischaemia resulting in upregulation of APP expression followed by Aβ deposition (Jendroska 1995). However, co‐existing pathology may occur independently of the disease process and increase the probability of exhibiting dementia in otherwise asymptomatic people (Riekse 2004).

Cholesterol and vascular dementia

VaD is the second most common form of dementia. It is characterised by both large and small vessel lesions. Subcortical ischaemic vascular disease caused by damage to tiny blood vessels that lie deep in the brain is now thought to be more prevalent than multi‐infarct dementia caused by large vessel lesions and stroke (Ballard 2000; Esiri 1997).

Sclerosis of small cerebral arteries and arterioles is considered to be responsible for the diffuse periventricular white matter abnormalities involved in the pathogenesis of subcortical VaD (Ryglewicz 2002). Risk factors for VaD are similar to risk factors for all types of vascular disease, namely hypertension, diabetes, smoking and hypercholesterolaemia (Ott 1998; Posner 2002; Stewart 1999). These factors are also important in the pathogenesis of AD (Decarli 2004); furthermore, the effects of vascular and AD pathologies are additive and in most population samples these disorders appear together (Snowdon 1997).

Plasma lipids could be associated with the risk of VaD through several mechanisms. High levels of LDL‐C and low levels of HDL‐C are established risk factors for coronary heart disease (Moroney 1999) and carotid artery atherosclerosis (Sharrett 1994). These may lead to cognitive impairment through cerebral hypoperfusion or embolism (Breteler 1994). LDL‐C may interact with ApoE to cause small vessel disease, and low levels of antioxidants known to occur in brains of people with VaD may lead to a higher susceptibility to oxidative stress and a higher grade of LDL‐C oxidation (Dantoine 2002; Paragh 2002).

One previous cross‐sectional analysis showed that the prevalence of VaD decreased with higher levels of HDL‐C and increased with higher levels of non‐HDL‐C. However, treatment with LLAs was not associated with the risk of prevalent VaD. Incidence of VaD was also calculated, again risk of VaD increased with increasing non‐HDL level but treatment with LLAs did not lower the risk of incident VaD (Reitz 2004). Other studies have found an association of VaD with decreased levels of HDL‐C (Kuriyama 1994; Muckle 1985; Zuliani 2001). The role of LDL‐C remains controversial, with some studies finding an association between increased LDL‐C and risk of VaD (Klich‐Raczka 2002; Moroney 1999; Paragh 2002), and other studies reporting a negative association (van Exel 2002; Yoshitake 1995).

Stroke is also a major risk factor for VaD. Debate continues as to whether increased cholesterol levels are a risk factor for stroke. Clinical trials indicated that statins significantly decreased stroke risk in vascular patients including patients with stroke (CTTC 2005; SPARCL 2006). The meta‐analysis carried out by the Cholesterol Treatment Trialists' Collaborators including 90,056 participants found that the use of statins caused a significant 17% proportional reduction in the incidence of first‐ever stroke of any type per 1 mmol/L LDL‐C reduction (CTTC 2005). In the secondary prevention of stroke, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study showed that treatment with atorvastatin reduced the risk of recurrent cerebrovascular events in people with recent stroke or transient ischaemic attack but no history of heart disease (SPARCL 2006). By reducing the risk of stroke, statins may also act to reduce the incidence of post‐stroke dementia.

Statins

Statins are a class of drugs that inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase. HMG‐CoA reductase 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. Several studies in cell culture and animals have demonstrated that treatment with cholesterol‐lowering drugs reduces the production of Aβ (Fassbender 2001; Refolo 2001; Simons 1998). It was therefore hypothesised that reduction of Aβ levels by statins may have neuroprotective effects in patients with AD (Simons 2001; Wolozin 2001). However, one study of transgenic mice found that levels of Aβ in the brains of simvastatin‐treated mice did not differ from those of untreated mice. Simvastatin treatment did lead to the reversal of learning and memory deficits and the authors hypothesised that the benefit of simvastatin may have been due to modulation of signalling pathways in memory formation (Li 2006). However, further work then demonstrated an association between antecedent statin use and neurofibrillary tangle burden at autopsy with risk for typical AD pathology reduced in statin users (Li 2007). The effects of statins on AD neuropathology are therefore not totally understood. Their possible role in the treatment of VaD includes secondary prevention of stroke and other pleiotropic effects as detailed below.

Statins are classified according to their solubility in lipids (lipophilic) or water (hydrophilic). Lipophilic statins (lovastatin, simvastatin, atorvastatin, fluvastatin) cross the BBB and penetrate cell membranes more effectively than hydrophilic statins and may be more efficient theoretically in the treatment of dementia than the hydrophilic statins (pravastatin). However, in contrast, reducing cholesterol synthesis below a critical level can induce neuronal death (Michikawa 1998), and may paradoxically make treatment with hydrophilic statins more appropriate (Sparks 2006).

Statins also have pleiotropic effects. They can improve the endothelial function of atherosclerotic vessels by decreasing endothelial 1 and angiotensin II type 1 receptors and increasing nitric oxide (Wassmann 2001). Low nitric oxide levels lead to impaired endothelial function, platelet aggregation and enhanced leukocyte adhesion to the endothelium. Statins also have antithrombotic effects as they decrease plasminogen activator levels and have anti‐inflammatory effects as they decrease adhesion molecules (Reitz 2004). They may also have the ability to reduce apoptosis and cellular death (Ruocco 2002). Many of these cholesterol‐independent effects reflect the ability of statins to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signalling molecules (Liao 2002).

It is also possible that reduced cholesterol synthesis and concentration in the CNS caused by treatment with statins may cause neurocognitive deficits. Several investigators have therefore questioned the potential detrimental effects of lowering cholesterol on cognition (King 2003; Muldoon 2000; Wagstaff 2003; Zhang 2004). It has been shown that large doses of statins can produce substantial neurotoxicity in dogs (Berry 1988; Walsh 1996). Statins lower circulating levels of vitamin E and ubiquinone (Coenzyme Q10) and may affect the synthesis of polyunsaturated fatty acids that are integral to neuronal membranes (Palomaki 1997; Rise 1997). Researchers have speculated that low concentrations of one or more components of lipoprotein particles circulating in the bloodstream may produce subtle but measurable impairments of mental processes by influencing the supply of fat‐soluble micronutrients, specifically, vitamin E, β‐carotene and vitamin A (Muldoon 1997). However, on balance, potential benefits from statins appear to outweigh potential detrimental effects and we will assess adverse effects from statins in this review.

Statins are widely available and prescribed for treatment of dyslipidaemia and secondary prevention of cardiovascular and cerebrovascular disease. Their cost is relatively low and some have come off patent so are prescribed generically.

Statin treatment in dementia

The use of statin therapy in established AD or VaD is a relatively unexplored area. There have been a number of studies on the role of statins in the prevention of dementia but these are the focus of another Cochrane review (McGuinness 2009). Further trials have followed patients with AD and dementia; these are the focus of this review and are presented in the results section.

One post‐hoc analysis on data pooled from three double‐blind placebo‐controlled clinical trials of galantamine in AD showed no significant change in cognitive status in association with the use of statins (Winblad 2007).

One observational study in patients with AD followed for 34.8 months showed that patients treated with LLAs had a slower decline on the Mini Mental State Examination (MMSE) than patients with untreated dyslipidaemia or normolipidaemic patients. The study concluded that LLAs (including fibrates and statins) may slow cognitive decline in patients with AD and may have a neuroprotective effect, but this finding needs to be confirmed by randomised placebo‐controlled trials (Masse 2005).

Patients with mild cognitive impairment (MCI) at baseline in the observational Ginkgo Evaluation of Memory Study showed no significant cognitive benefit from treatment with LLAs including statins. This was in contrast to people without MCI at baseline who showed a reduced risk of all‐cause dementia and AD (Betterman 2012).

Other LLAs (fibrates, niacin/nicotinic acid, anion‐exchange resins) have been assessed with statins in several dementia studies. Fibrates are the main class in use other than statins. Rockwood et al. published a population‐based survey from the Canadian Study of Health and Aging (CSHA) demonstrating use of statins and other LLAs on reduced risk of AD in people younger than 80 years old (Rockwood 2002). In contrast, the UK General Practice Research Database study showed that only statins reduced the risk of dementia, other LLAs did not (Jick 2000). In a further study in patients with AD, all LLAs including statins were associated with a slower annual cognitive decline but there was no significant difference between statins and other LLAs and there was lack of statistical power to compare statins to fibrates (Masse 2005).

Fibrates do not inhibit cholesterol biosynthesis, they stimulate β‐oxidation of fatty acids and act mainly by decreasing serum triglycerides. They are only used first line in people with hypertriglyceridaemia and can be used in combination with statins in people not responding to single therapy. Fibrates also have anti‐inflammatory effects as they inhibit the production of different pro‐inflammatory molecules (Pahan 2006). However, in this review, we were primarily interested in role of statins in the treatment of dementia.

This review aimed to collate the best available evidence regarding use of statins in AD and VaD.

Statins decrease coronary events in the primary and secondary prevention of coronary heart disease significantly. The question is whether they have a significant therapeutic effect in dementia. Any intervention shown to slow the progression of dementia would have huge worldwide economic benefit.