It is amazing to consider the amount of damage being done by the pursuit of the medical dogma that our heroic ‘cholesterol’ molecules got involved in pathogenesis. Tomorrow I will wake up and the ‘Medical Nightmare’ of blaming fats and cholesterol for CVD will be over.

Synaptogenesis and neural cholesterol

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 (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 followup was demonstrated [40].

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 DJ, Park SW, Kaang BK. 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; 283: 230-4.
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 gliaderived
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 wellbeing.
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, placebocontrolled,
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; 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.

it is worrying to think about how subtle changes in senior politicians behaviours may be caused by their medications.

The neurological effects of cholesterol depletion can produce a wide range of mental conditions reported to be associated with serum cholesterol depletion. Depression, violent behaviour, homicidal
behaviour and suicide are all known associates of cholesterol depletion [58, 59]. In a recent study, cholesterol content was measured in cortical and subcortical tissue of brains from 41 male suicide completers and 21 male controls. Violent suicides were found to have lower gray matter cholesterol content overall compared with nonviolent suicides and controls [60]. Randomised trials with statins have not shown a definite association between cholesterol-lowering
treatment and non-illness mortality from suicides, accidents, and violence [61, 62]. However, statin trials are specifically designed to test drug efficacy, often with run-in phases, and investigators usually
conduct the studies in groups of patients who have few comorbidities and are not using many concomitant medications, and when side effects are measured, their seriousness and severity are not graded. Indeed, in clinical practice it has been suggested that severe anger and irritability may occour in some statin users [63].
Neural systems have significant vulnerability to cholesterol depletion. First is the reduction in the synaptic exocytosis and endocytosis of essential signalling lipoproteins; then comes the vulnerability due to the high dependency of myelination on denovo cholesterol biosynthesis.

58. Lester D. Serum cholesterol levels and suicide: a metaanalysis.
Suicide Life Threat Behav 2002; 32: 333-46.
59. Edgar PF, Hooper AJ, Poa NR, Burnett JR. Violent behavior
associated with hypocholesterolemia due to a novel APOB
gene mutation. Mol Psychiatry 2007; 12: 258-63.
60. Lalovic A, Levy E, Luheshi G, et al. Cholesterol content in
brains of suicide completers. Int J Neuropsychopharmacol
2007; 10: 159-66.
61. Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle
SH. Cholesterol reduction and non-illness mortality: metaanalysis
of randomised clinical trials. BMJ 2001; 322: 11-5.
62. Baigent C, Keech A, Kearney PM, et al.; Cholesterol
Treatment Trialists’ (CTT) Collaborators. Efficacy and safety
of cholesterol-lowering treatment: prospective metaanalysis
of data from 90,056 participants in 14
randomised trials of statins. Lancet 2005; 366: 1267-78.
63. Golomb BA, Kane T, Dimsdale JE. Severe irritability
associated with statin cholesterol-lowering drugs. QJM
2004; 97: 229-35.