Statins and Their Preventative Effects of Alzheimer’s Disease

Hey all, here is a review I wrote about Statins and Alzheimer’s disease. Leave comments below, let’s start a discussion.


Alzheimer’s disease is a major health issue in America, given there were approximately 5 million Americans living with Alzheimer’s Disease in 2013.By the year 2050 the CDC has estimated that the approximate number of individuals in the United States diagnosed with Alzheimer’s Disease will reach 14 million people, a three-fold increase ( Alzheimer’s disease affects everyone, with the cost of Alzheimer’s disease overall being $214 billion, of which $37 billion from Medicaid and $113 billion from Medicare. The cost is proliferating at an alarming rate, with the 2050 expectation of cost to be $1.2 trillion (Alzheimer’s Association).

Vascular disease and more specifically hypercholesterolemia (high cholesterol), is also an American health crisis. Hypocholesterolemia affects approximately 71 million americans, or approximately one-third of America’s adult. Hypercholesterolemia is typically correlated with poor dietary choices, genetic predispositions, and lack of exercise (

A growing amount of research to back claims that high cholesterol increases a person’s chances of developing the neurodegenerative disease, The use of statins to lower cholesterol has shown a connection between the administration of statins and Alzhiemr’s Disease. Statins are cholesterol lowering drugs which work by interfering with cholesterol formation via inhibition of the enzyme HMG- CoA reductase, an active enzyme that produces cholesterol (Puglielli, Tanzi, and Kovacs, 2003). The objective of this review is to further comment upon the current research in the field linking together cholesterol levels, Alzheimer’s Disease and statins, as well as discuss some of the adverse effects of statin administration.

Alzheimer’s Disease: Beta-Amyloid Plaques

Beta amyloid plaques are a pathological hallmark of Alzheimer’s disease. They consist of aggregated 40-42 amino acids clumped together (Seeman and Seeman 2011). The question that has been answered by Hass, Hung, and Selkoe (1991) is, where are these proteins coming from? They deduced that the main source of beta amyloid 42 is the breakdown of the amyloid precursor protein, which is localized in the cellular membrane and their intracellular vesicles of many types of cells (Haass, Hung, Selkoe, 1991). Here, the main focus will be upon neurons.

Beta-amyloid 40 and 42 are given such names to recognize at which specific amino acid they are produced via the cleaving of amyloid precursor proteins (APP).Cleavage of APP occurs via the enzyme beta-secretase. APP can also be cleaved by gamma secretase at the 40 and 42 amino acid positions. Once it is cleaved it has a rapid rate of release into the extracellular space. The approximate rate of beta-amyloid 40/42 release is 2-4 molecules of beta amyloid per neuron per second within cultured neurons (Moghekar, Li, Ruben, Mammen, Tang, O’Brien 2011). The problem with the quick rate of beta amyloid being produced so swiftly is that it may progress Alzheimer’s disease at an exponential rate.

Beta-amyloid can then be picked up by plasma and cerebral spinal fluid (CSF). Blood platelets have been shown to be a primary source of beta-amyloid distribution throughout the brain (Chen, Inestrosa, Ross, Fernandez, 1995). Once within the plasma beta-amyloid can be absorbed into the cellular membrane of neurons (Burdick, Kosmoski, Knauer, Glabe, 1997). Once the beta amyloid has been integrated into the cellular membrane it can then begin to aggregate with other beta amyloid 40/42 mis-folded proteins because of their high propensity to cluster together (Chiti and Dobson, 2006; Sandber et al., 2010; Soreghan, Kosmoski, Glabe, 1994). Beta amyloid aggregation can further affect neurons because that it causes calcium channels to open, impair long term potentiation, and decrease synaptic spines which in turn can lead to cell death (Bhatia, Lin, Lal 2000; Lin, Bhatia, Lal, 2001; Jacobsen et al., 2006; Thomas et al., 1996; Xu et al., 2001). However, it has been shown that aggregation of beta amyloid plaques and thus the severity of aggregation is not significantly correlated with dementia severity (Tamayev, Matsuda, Fa’ M, Arancio, D’Adamio 2010).


Alzhiemer’s Disease: Cholesterol in the Brain

It has been found that cholesterol has its highest concentration within the brain, approximately 30g. Combining the liver and blood plasma only have approximately 5g of cholesterol collectively (Crisby, Carlson, Winblad, 2002). In order to fully understand how cholesterol functions within the brain it is important to understand the cholesterol synthesis process within the brain. First acetoacetyl CoA condenses with acetyl CoA producing mavelonate which is only produced in the presence of 3-hydroxyl-3-methylglutaryl (HMG) synthase and HMG-CoA reductase. After cholesterol is produced it is then secreted and can then bind to apolipoproteins and form lipid protein complexes ready for transport which can either be in the form of high density lipoprotein complexes (HDL) or low density lipoprotein complexes (LDL). In individuals with Alzheimer’s disease we see a decrease in an essential enzyme found in blood plasma called lecithin-cholesterol acyltransferase (LCAT). LCAT is responsible for catalyzing an acetyltransferase reaction upon lipoprotroteins associated with cholesterol thus further metabolizing cholesterol (Knebl, DeFazio, Clearfield, Little, McConathy, Mc Pherson, Lacko, 1993).These lipoprotein receptors, specifically LDL are the most abundant and allow for cholesterol to be recycled through the endoplasmic reticulum. However, if the apolipoprotein variant E4 is expressed in a person cholesterol uptake can be disrupted. (Wolozin, 2004; Herz and Strickland, 2001). ApoE4 may disrupt brain cholesterol homeostasis via modifications of lipoprotein particle formation. This occurs because ApoE4 is more associative with vesicular LDL (VLDL) particles that transport cholesterol (Ehnholm, Lukka, Kuusi, Uterman 1986; Boerwinkle et al., 1987).

Refolo and colleagues (2000) have shown that hypercholesterolemia accelerates Alzheimer’s disease . These findings have shown in an epidemiologic study that disturbance within cholesterol metabolism is directly linked to Alzheimer’s susceptibility (Refolo et al., 2000). Furthermore, oxidative stress is involved in the pathogenesis of AD and atherosclerosis. This is important because oxidation of LDL receptors generates reactive oxygen species (ROS) and proinflammatory lipoprotein mediators, contributing to the disease and instability of blood vessel walls. Instability of blood vessel walls has been shown to increase the rate at which the pathogenesis of Alzheimer’s disease occurs. (Steinberg and Witztum, 1991). Increasing ROS has also been involved in the cell damage of AD (Smith et al., 2002). Building upon the idea that ROS and proinflammatory lipoprotein mediators disturbing brain vasculature, we also see that if brain vasculature is disturbed that this may contribute to progression of Alzheimer’s disease (De la Torre, 1997).

Cholesterol and Beta amyloid (the main hallmark of Alzheimer’s disease) can be found coexisting with one another within the brain. Miyakawa and colleagues (1982) have shown that this is a strong proximal relationship between Alzheimer’s plaques and blood vessels in the brain. Studies have provided supporting data that increasing cholesterol and therefore ROS and pro-inflammatory lipoporotein mediators weaken vessel walls and then produce cholesterol aggregation inside amyloid plaques (Puglielli, Tanzi, Kovacs, 2003; Steinberg and Witztum, 1991). High cholesterol is a main proponent of ischemic heart disease has been seen in patients whom upon death and autopsy shown similar deposits of amyloid beta plaques as that as a person with Alzheimer’s disease(Sparks et al., 1990). Wolozin (2004) has suggested that cholesterol catabolism is dependent upon ABCA1, Cyp 46, and ACAT, which have been shown to also reduce beta amyloid secretion. Studies in mice have shown that amyloid precursor protein (APP) can be regulated by cholesterol and thus regulate beta-amyloid generation (Bales et al., 1999; Holtzman et al., 2000). This further shows how interwoven cholesterol and beta amyloid deposition are.

Azlheimer’s Disease: Apolipoprotein E and Cholesterol

Apolipoprotein E (ApoE) is a group of proteins that are responsible for binding to lipids to form larger structures called lipoproteins (Poirier et al., 1993). ApoE can be found on the long arm of chromosome 19 with common polymorphisms as follows: E2, E3, and E4 (Mahley, 1988). ApoE is seen as a vital group of proteins because of it’s ability to traffic cholesterol as well as repair, encourage growth and maintenance of myelin and neuronal membranes during development or after injury (Mahey, 1988; Boyle et al., 1989). However, in individual possessing the E4 variant of apolipoprotein cholesterol is not readily eliminated and can therefore aggregate (Poirier 1993). Apolipoprotein, specifically the E4 variant, has been shown by Poirier et al (1993) in a longitudinal study individuals have an increased incidence rating of approximately 3-fold that the normal incidence rating for developing Alzheimer’s disease. ApoE(4) mRNA has been found to bind tightly to Beta-amyloid (Wisniewski and Frangione, 1991; Wisniewski et al., 1993; Strittmatter et al., 1977; Namba et al., 1991). Unsuprisingly, apolipoproteins variant E4 are typically found in amyloid plaques (Namba, Tomonaga, Kawasaki 1991; Wisniewski and Frangione, 1991). ApoE4 has been shown to have a high affinity to bind to LDL receptors which are receptors that are required for mevalonate to produce its byproducts and thus the esterification of cholesterol (Ehnholm, Lukka, Kuusi, Nikkila, Utermann, 1986; Boerwinkle et al., 1987; Mahley 1988). Individuals with the genetic predisposition for ApoE4 also have a higher presence of plasma cholesterol lipoprotein levels (Poirier, Hess, May, Finch, 1991; Poirier, Baccichet, Dea, Gautheir, 1993). These findings further provide evidence that there is a connection between cholesterol and apolipoproteins and cholesterol and thus Alzheimer’s disease and cholesterol.

The Statin Connection and Preventative Factors

Statins are HMG-CoA reductase inhibitors, meaning that they disrupt the production of low density lipoproteins (Tolmach-Sugerman 2013). Therefore statins act directly on HMG-CoA reductase which is essential for the synthesis of cholesterol. Statins can also use alternative routes so as to disrupt cholesterol synthesis. Statins are able to inhibit cholesterol ester accumulation via inhibition of LDL endocytosis which can in turn inhibit and reduce the formation of mevalonate which is required for cholesterol esterification. Statins have also been shown to reduce free cholesterol molecules, which are active components in LDL (Bernini ,1993).

Animal studies show that as statins are administered there is an increase in alpha secretase and therefore a decrease in beta amyloid expression (Buxbaum, Geoghagen, Friedhoff, 2001). It has also been observed that statins may help prevent the cleavage of amyloid precursor proteins which would in turn form beta amyloid (Kirsch, Eckert, Mueller, 2003). Both of these findings would in turn lower the prevalence of Alzheimer’s disease. However, it has been shown by Höglund and colleagues (2004) that neither beta-amyloid _40/42 were significantly affected by simvastatin nor atorvastatin. These results seem to hold true and is with agreement when looking at cerebral spinal fluid concentrations of beta amyloid which were unaffected via administration of statins, within a hypercholesterolemia population (Fassbender et al., 2002). This also holds true when observing the total beta amyloid levels within the previous mentioned study (Höglund et al., 2004). Höglund and colleagues (2004) did however show a reduction in cholesterol due to atorvastatin and simvastatin with the reduction being 53% and 57% respectively.


Statins are an exciting and new approach to treating Alzheimer’s disease. While the use of statins may seem a promising route, there have been a number of contradictions amongst researchers in the field. Upon epidemiological research, case control studies have shown that statin users had lowered risks of dementia (Table 1) (Jick, Zornberg, Jick, Seshadri, Drachman, 2000; Hajjar, Schumpert, Hirth, Wieland, Eleazer, 2002; Rockwood et al., 2002). However, there have been studies that have shown that there is not a significant effect of Alzheimer’s disease reduction in prevalence through the use of statins (Table 1) (Rea et al., 2005; Li et al., 2004; Zandi et al., 2005). Although, when the authors simulated case control designs, statins were associated with lower risk of AD (Rea et al., 2005; Li et al., 2004). Possibly this could mean that the significance found in the epidemiological studies showing that statins were lowering the prevalence of Alzheimer’s disease is just a statistical phenomena. More research is needed to look at both the adverse health effects of statins as well as the efficacy of such drugs.


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 (Kandiah &Feldman, 2009)

(Kandiah &Feldman, 2009)

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