Tag Archives: alzheimers

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Current guidelines encourage ambitious long term cholesterol lowering with statins, in order to decrease cardiovascular disease events. However, by regulating the biosynthesis of cholesterol we potentially change the form and function of every cell membrane from the head to the toe. As research…

Nowhere is the impact of cholesterol depletion more keenly studied than in the neurologic arena.   

The work of Pfrieger et al. described the functional role of cholesterol in memory through synaptogenesis [24]. Mauch et al. [25] reported evidence that cholesterol is vital to the formation and correct operation of neurons to such an extent that neurons require additional sources of cholesterol to be secreted by glial cells. A recent mini-review by Jang et al. describes the synaptic vesicle secretion in neurons and its dependence upon cholesterol-rich membrane areas of the synaptic membrane [26]. Furthermore, working on rat brain synaptosomes, Waseem [23] demonstrated that a mere 9.3% decrease in the cholesterol level of the synaptosomal plasma membrane could inhibit exocytosis. These data might be particularly worrisome for lovastatin and simvastatin which are known to cross the blood brain barrier [27].

In fact, the proposed use of statins as a therapeutic agent in Alzheimer’s Disease (AD) [28] counters Pfrieger’s evidence [24]. Indeed, a reduction in cholesterol synthesis leads to depletion of cholesterol in the lipid rafts – i.e. the de-novo cholesterol is required in the neurons for synaptic function and also in the neuronal membrane fusion pores [29].

Cognitive problems are the second most frequent type of adverse events, after muscle complaints, to be reported with statin therapy [30] and this has speculatively been attributed to mitochondrial effects. The central nervous sytem (CNS) cholesterol is synthesised in situ and CNS neurons only produce enough cholesterol to survive. The substantial amounts needed for synaptogenesis have to be supplemented by the glia cells. Having previously shown that in rat retinal ganglion cells without glia cells fewer and less efficient synapses could form, Göritz et al. [31] indicate that limiting cholesterol availability from glia directly affects the ability of CNS neurons to create synapses. They note that synthesis, uptake and transport of cholesterol directly impacts the development and plasticity of the synaptic circuitry. We note their very strong implication that local de-novo cholesterol synthesis in situ is essential in the creation and maintenance of memory..  

There should be further consideration of cholesterol depletion on synaptogenesis, behaviours and memory loss for patients undergoing long-term statin therapy. This is particularly important with lipophilic statins which easily cross the blood brain barrier [32].

The effects of statins on cognitive function and the therapeutic potential of statins in Alzheimer´s disease are not clearly understood [28]. Two randomised trials of statins versus placebo in relatively younger healthier samples (lovastatin in one, simvastatin in other) showed significant worsening of cognitive indices relative to placebo [33, 34]. On the other hand, two trials in Alzheimer samples (with atorvastatin and simvastatin respectively) suggested possible trends to cognitive benefit, although these appeared to dissipate at 1 year [35, 36]. A recent Cochrane review concluded that there is good evidence from randomised trials that statins given in late life to individuals at risk of vascular disease have no effect in preventing Alzheimer´s disease or dementia [37]. However, case reports and case series from clinical practice in the real world reported cognitive loss on statins that resolved with discontinuation and recurred with rechallenge [30].

Evidence from observational data and prestatin hypolipidemic randomised trials showed higher hemorrhagic stroke risk with low cholesterol [30]. In fact, in the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial as compared with placebo, the use of high-dose atorvastatin was associated with a 66% increase in the relative risk of hemorrhagic stroke among the patients receiving the statin drug [38]. In addition to treatment with atorvastatin, an exploratory analysis of the SPARCL trial found that having hemorrhagic stroke as an entry event, male sex, and advancing age at baseline accounted for the great majority of the increased risk of hemorrhagic strokes [39]. However, a sensitivity analysis excluding all patients with a hemorrhagic stroke as an entry event in the SPARCL trial found that statin treatment was still associated with an increased risk of hemorrhagic stroke [40]. Furthermore, in a subgroup of patients with a history of cerebrovascular disease enrolled in the Heart Protection Study [41] which did not include patients with hemorrhagic stroke, a similar increased risk of hemorrhagic stroke during follow-up was demonstrated [40].

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[24] Pfrieger FW. Role of cholesterol in synapse formation and function Biochim Biophys Acta 2003; 1610: 271-80.

[25] Mauch DH, Nägler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol Science 2001; 294: 1354-7.

[26] Jang D, Park S, Kaang B. The role of lipid binding for the targeting of synaptic proteins into synaptic vesicles BMB Rep 2009; 42: 1-5.

[27] Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors Pharm Res 1994; 11: 305-11.

[28] Kandiah N, Feldman HH. Therapeutic potential of statins in Alzheimer’s disease. J Neurol Sci. 2009 Mar 23. [Epub ahead of print].

[29] Jeremic A, Jin Cho W, Jena BP. Cholesterol is critical to the integrity of neuronal porosome/fusion pore Ultramicroscopy 2006; 106: 674-7.

[30] Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism Am J Cardiovasc Drugs 2008; 8: 373-418.

[31] Göritz C, Mauch DH, Nägler K, Pfrieger FW. Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair J Physiol Paris 2002; 96: 257-63.

[32] Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ. Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord 2006; 22: 392-8.

[33] Muldoon MF, Barger SD, Ryan CM. et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med 2000; 108: 538-46.

[34] Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 2004; 117: 823-9.

[35] Sparks DL, Sabbagh M, Connor D, et al. Statin therapy in Alzheimer’s disease. Acta Neurol Scand Suppl 2006; 185: 78-86.

[36] Simons M, Schwärzler F, Lütjohann D, et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002; 52: 346-50.

[37] McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev 2009 Apr 15; (2): CD003160.

[38] Amarenco P, Bogousslavsky J, Callahan A 3rd, et al.; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-59.

[39] Goldstein LB, Amarenco P, Szarek M, et al.; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008; 70:2364-70.

[40] Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39:497-502.

[41] Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757–67.

Synaptogenesis and Neural Cholesterol

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The Bio-chemical Science pages of Glyn Wainwright, Publisher, Independent Reader of Research and Honorary Recording Engineer for Leeds Symphony Orchestra<

Anecdote: A  diabetic clinician told me she had noticed that when patients had good control of their hba1c (an indicator of sugar-damage in blood ) their ‘cholesterol’ score also improved.

Every molecule of cholesterol in the body is known to be identical to every other. 

The Good/Bad labeling of cholesterol is extremely unscientific and unhelpful, and that is a matter of scientific fact.

How were  intelligent, well educated, medical professionals  persuaded to popularise this ‘Good ‘ cholesterol versus  ’Bad’ cholesterol idea?

The unscientific phrase ‘Bad Cholesterol’ is a misleading description of damage to the ’lipid transport system ‘, whose basic function was described by the Nobel Prize winners James E. Rothman, Randy W. Schekman and Thomas C. Südhof.  (Awarded “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells”.

The lipid transport system is used by the body to deliver essential supplies of fat, cholesterol, and other fat-soluble nutrients.

The lipid transport system is able to repair and recycle, but can be progressively overwhelmed by the damage accumulated over several decades.

This  damage to the lipid system is caused by oxidation and glycation: the result of excessive consumption of refined sugars (in particular High Fructose syrups).

It is not ‘bad cholesterol’ but sugar-damage to the proteins that make the lipids available to the organs of our body.

Unconsumed ‘damaged’ ldl  in the blood is an indicator of trouble because the organs are being starved  of vital fats cholesterol and fat-soluble nutrients.

‘Bad Medicine’ prevents the liver and all other organs from making essential cholesterol   indirectly stop the supply of lipids to the blood.

Cholesterol lowering medications have a variety of very broad variety of adverse-effects, all attributable to organs being starved of fat, cholesterol and fat-soluble nutrients.

The ‘bad medicine’s do not tackle the cause of damage to the ldl –  lipids supply.

The primary cause of this ldl damage is the oxidation and glycation of the  ldl’s components.

The main dietary and lifestyle causes of ldl damage are over-consumption of refined sugars and inactivity.

The reactive sugars like fructose, found in manufactured corn syrups are particularly troublesome, because they directly attach to ldl-protein mechanisms causing a mal-function which starves the organs.

Important protective and anti-oxidant functions rely on Cholesterol and CoQ10 –  both of which  are reduced  anti-cholesterol medications. 

The unscientific use of the incorrect description ‘Bad Cholesterol’ has held back medicine for over 40 years and it is time to look at the evidence in more detail:-

“Cholesterol Lowering Therapies and Membrane Cholesterol”   Wainwright G Mascitelli L  &  Goldstein M R, Archives of Medical Science, Vol. 5 Issue 3 p289-295 2009

“Is the metabolic syndrome caused by a high fructose, and relatively low fat, low cholesterol diet?”   Seneff S, Wainwright G, and Mascitelli L Archives of Medical Science  Vol. 7 Issue 1 p8-20 2011 doi: 10.5114/aoms.2011.20598

 "Nutrition and Alzheimer’s disease: the detrimental role of a high carbohydrate diet"   Seneff S., Wainwright G., and Mascitelli L. European Journal of Internal Medicine 2011, doi:10.1016/j.ejim.2010.12.0172011

‘Good/Bad Cholesterol ‘ and ‘Bad Medicine’

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Key points in our paper are:-

The amyloid-β present in Alzheimer’s plaque may not be causal,
since drug-induced suppression of its synthesis led to further
cognitive decline in the controlled studies performed so far.

• Researchers have identified mitochondrial dysfunction and brain
insulin resistance as early indicators of Alzheimer’s disease.
• ApoE-4 is a risk factor for Alzheimer’s disease, and ApoE is involved
in the transport of cholesterol and fats, which are essential for signal
transduction and protection from oxidative damage.
• The cerebrospinal fluid of Alzheimer’s brains is deficient in fats and
cholesterol.
• Advanced glycation end-products (AGEs) are present in significant
amounts in Alzheimer’s brains.
• Fructose, an increasingly pervasive sweetening agent, is ten times as
reactive as glucose in inducing AGEs.
• Astrocytes play an important role in providing fat and cholesterol to
neurons.
• Glycation damage interferes with the LDL-mediated delivery of fats
and cholesterol to astrocytes, and therefore, indirectly, to neurons.
• ApoE induces synthesis of Aβ when lipid supply is deficient.
• Aβ redirects neuron metabolism towards other substrates besides
glucose, by interferingwith glucose and oxygen supply and increasing
bioavailability of lactate and ketone bodies.
• Synthesis of the neurotransmitter, glutamate, is increased when
cholesterol is deficient, and glutamate is a potent oxidizing agent.
• Over time, neurons become severely damaged due to chronic exposure
to glucose and oxidizing agents, and are programmed for apoptosis
due to highly impaired function.
• Once sufficiently many neurons are destroyed, cognitive decline is
manifested.
• Simple dietary modification, towards fewer highly-processed
carbohydrates and relatively more fats and cholesterol, is likely a
protective measure against Alzheimer’s disease.

Fructose and Dementias

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The brain is only 2% of your body mass but it contains 25% of your cholesterol.  The cholesterol is vital to memory formation (synapses)  and nerve protection (myelin).  Our livers make 2.5g of fresh cholesterol every day to replace the losses.  The liver delivers the brains fresh daily supply of cholesterol to the brain in small lipid droplets known as LDL.  The empties return to the liver known as HDL with various waste products for recycling and disposal.

To get these vital supplies into the brain the LDL droplets have to cross the blood-brain barrier. The particles carry a protein label which is recognised by the receptors.  The brains receptors lock onto the LDL and allow the particles to pass though into the brains astrocyte cells. These astrocytes use the cholesterol  and fats in the care and feeding of the neurons and all is well with our thoughts and memories.

If we consume a lot of sugary products, especially fructose, the receptors become damaged by sugary attachments and fail to work.  The LDL then builds up in the blood and the brain is starved of fat and cholesterol.  All is now not well with our thoughts and memories.

This is a simplification of our biochemical papers on this matter. Other organs like the heart are also affected this way. How is it possible for an educated professionals to go on misleading us by referring to LDL as “Bad Cholesterol”?   

Fructose is getting away with murder and the blame is being laid upon the good guys  – fat and cholesterol.  

Please click on and read our free peer reviewed medical journal publications and ask your medical advisors some tough questions about this low cholesterol ‘madness’.

“Cholesterol Lowering Therapies and Membrane Cholesterol”

Wainwright G   Mascitelli L  &  Goldstein M R

Archives of Medical Science Vol. 5 Issue 3 p289-295 2009

“Is the metabolic syndrome caused by a high fructose, and relatively low fat, low cholesterol diet?”

 Seneff S, Wainwright G, and Mascitelli L

Archives of Medical Science  Vol. 7 Issue 1 p8-20 2011 doi: 10.5114/aoms.2011.20598

“Nutrition and Alzheimer’s disease: the detrimental role of a high carbohydrate diet”

Seneff S., Wainwright G., and Mascitelli L.

European Journal of Internal Medicine 2011  doi:10.1016/j.ejim.2010.12.0172011

Low Cholesterol – Madness

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Alzheimer’s disease is a devastating disease whose recent increase in incidence rates has broad implications for rising health care costs. Huge amounts of research money are currently being invested in seeking the underlying cause, with corresponding progress in understanding the disease progression. In this paper, we highlight how an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer’s disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency  in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate
signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. Other neurodegenerative diseases share many properties with Alzheimer’s disease, and may also be due in large part to this same underlying cause.

Dr Stephanie Seneff is a senior research scientist at MIT.

Alzheimer’s disease: The detrimental role of a high carbohydrate diet

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The world’s big pharmaceutical companies are cutting back their research into treatment for Alzheimer’s, after being hit by the failure of a number of high profile, and expensive, drugs trials. Sir John Bell, Life Sciences Champion for the government, and Stephen Whitehead, head of the Association of the British Pharmaceutical Industry discuss why it is proving so hard to find something that works.

BBC Radio4 Today: Thursday 20th September 07:50 BSTOur Paper on Alzheimers Disease
Source: lizscript.co.uk