Neurology -- Correspondence for Simons et al., 57 (6) 1089-1093

Correspondence published:

Reply to Letter to the Editor: Mikael Simons (15 March 2002)

Cholesterol and Alzheimer’s disease: Is there a link?: Siegfried Hoyer (15 March 2002)

Beware: the link is not simple: Alexei R Koudinov, "Temirbolat T Berezov, Natalia V Koudinova" (16 October 2001)

Reply to Letter to the Editor 15 March 2002

Mikael Simons
University of Tubingen Tubingen Germany
Send Correspondence to journal:
Re: Reply to Letter to the Editor

mika_simons{at}hotmail.com Mikael Simons

We appreciate the interest and the comments on our review by Dr. Hoyer. There is now accumulating evidence that deposition of Aā 40 and 42 into extracellular plaques triggers a cascade leading to a neurodegeneration in patients with AD. Reduction of cholesterol synthesis in cell culture and in guinea pigs decreases the production of Aā 40/42 [1] and reduces the plaque load in transgenic animals of AD. [3] Moreover, two recent retrospective clinical studies indicate that there is a decreased prevalence of dementia [4] or AD [5] associated with the use of statins to treat hypercholesterolemia.
Therefore, there is now substantial hope that cholesterol synthesis inhibitors, statins, might be beneficial for patients suffering from AD. [1] Dr. Hoyer raises the concern that treatment with statins in patients with AD may lead to loss of synapses and accelerate the disease process by reduction of cholesterol in the cell membrane. There is no doubt, that cholesterol is an essential component of the cell membrane and therefore important for brain function. However, there is no evidence that statins used at the recommended dose reduce cholesterol in the brain below a critical level. For example, simvastatin, one of the most brain-permeable statins, was used in the first large randomized trial of cholesterol lowering in 4444 patients (Te Scandinavian Simvastatin Survival Study), but no side effects related to dysfunction of the nervous system were reported. [6] In this study patients with atherosclerosis and hypercholesterolemia were tested, but not normocholesterolemic patients with AD. As Dr. Hoyer mentions brains of AD patients have different lipid compositions. If the amount of cholesterol would be specifically reduced in patients with AD, it might indeed be problematic to treat patients with AD with brain-permeable statins. However, several studies have shown that cholesterol levels are variable, but mostly unchanged in brains of patients with AD. [2, 7] We agree with Dr. Hoyer that so far there is not sufficient evidence for treating AD patients with statins. Only prospective clinical trials will answer the question whether statins slow down the progression of AD without disturbing the function and viability of neurons.
References:
1)Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and Alzheimer’s disease. Is there a link? Neurology 2001;57:1089-1093.
2)Svennerholm L, Gottfries CG. Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type 1) and demyelination in late-onset form (type II). J Neurochem 1994;62:1039-1047.
3)Refolo LM, Pappolla MA, Malester B, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 2000;7:321-331.
4)Jick H, Zornberg, GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000;356:1627-1631.
5)Wolozin B, Kellman W, Rousseau P, Celesia CC, Siegel G. Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3- methylglutaryl Coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439- 1443.
6)Scandinavian trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.
7)Soderberg M, Edlund C, Alafuzoff I, Kristensson K, Dallner G. Lipid composition in different regions of the brain in Alzheimer’s Disease/Senile Demential of Alzheimer’s Type J. Neurochemistry 1992;59:1646-1653.

Cholesterol and Alzheimer’s disease: Is there a link? 15 March 2002

Siegfried Hoyer
University of Heidelberg Heidelberg Germany
Send Correspondence to journal:
Re: Cholesterol and Alzheimer’s disease: Is there a link?

Siegfried_Hoyer{at}med.uni-heidelberg.de Siegfried Hoyer

Simons et al [1] discussed the relationship between brain cholesterol metabolism and AD with particular focus on Aā formation. Based on two retrospective clinical studies on a mixed dementia population (vascular dementia, sporadic Alzheimer dementia, secondary dementias) treated with statins they expressed the hope that such a treatment may inhibit intracellular cholesterol formation, and as a consequence, reduce Aā thus being beneficial for Alzheimer patients. This view was supported by investigations on both cell cultures of fetal hippocampal neurons and healthy adult guinea pigs both possessing intact cell membranes leading to reduced formation of Aā under the treatment of a statin applied in a dose 200 to 400 times greater than used in human beings.
Cholesterol is an essential constituent of membranes and guarantees and stabilized their function and structure. Membranes in Alzheimer brains were found to be severely damaged in their lipid composition including cholesterol, which was demonstrated to be reduced in different brain areas. [2] In post-mortem Alzheimer brains, the unesterified cholesterol: phospholipid mole ratio decreased by 30 % in the temporal gurus, and this lower membrane cholesterol content is assumed to cause an average 4Ǻ reduction in the lipid bilayer width modulating the biophysical properties of such damaged membranes. [3] The reduction of both cellular formation due to a lack of acetyl CoA and membrane concentration of cholesterol in Alzheimer brains are mirrored by a decrease of cholesterol concentration in CSF. [4] The neuron’s capacity to form synapses depends on the availability of cholesterol, which is mainly provided by glia cells. [5] Unquestionably, AD was found to be associated with a severe synapse loss as a predominant morphologic abnormality. Although not studied in detail as yet, there is a great likelihood that the reduction in synapse membrane cholesterol concentration contributes to the degeneration and loss of synapses in AD. Taken together, there is a link between cholesterol and AD.
However, this link has a different meaning as suggested by Simons et al. [1] all the more so since Aā in the CSF of Alzheimer patients declines in the spontaneous course of the disease. Statins applied to Alzheimer patients may increase the destabilization of brain membranes. Therefore, there may be no rationale for statin treatment of AD.
References:
1)Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and Alzheimer’s disease. Is there a link? Neurology 2001;57:1089-1093.
2)Svennerholm L, Gottfries CG. Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type 1) and demyelination in late-onset form (type II). J Neurochem 1994;62:1039-1047.
3)Mason, RP, Shoemaker, WJ, Shajenko K, Chambers TE, Herbette LG. Evidence for changes in the Alzheimer’s disease brain cortical membrane structure mediated by cholesterol. Neurobio Aging 1992;13:413-419.
4)Mulder M, Ravid R, Swaab DF et al. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebral spinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis Ass Disord 1998;12:198-203.
5)Mauch Dh, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001;294:1354-1357.

Beware: the link is not simple 16 October 2001

Alexei R Koudinov,
neuroscientists
Russian Acad Med Sciences, Moscow, Russia; Weizmann Inst., Dept. Biol. Regulation, Rehovot, Israel,
"Temirbolat T Berezov, Natalia V Koudinova"
Send Correspondence to journal:
Re: Beware: the link is not simple

koudin{at}imb.ac.ru Alexei R Koudinov, et al.

We read with great interest the article by Simons et al. ( Neurology 2001, 57: 1089-1093 ) entitled “Cholesterol and Alzheimer’s disease: is there a link?”. In 1994, we reported an association of soluble form of amyloid b protein with high density lipoproteins and functional role for amyloid b in cholesterol esterification and lipid synthesis [ 1 ].
However, it is premature to make definite conclusions on the beneficial role of cholesterol lowering in Alzheimer’s patients. This is because understudied neuronal cholesterol functional biochemistry is not that clear. The effect of statins on cognitive function is also unclear. [ 2 ].
It is possible that cholesterol homeostasis failure itself plays a primary role for neurotransmission and synaptic plasticity failure, and Alzheimer’s like neuronal degeneration [ 3 ]. Thus, cholesterol pathology may represent the primary cause for several Alzheimer’s disease hallmarks not limited to brain amyloid [ 4 ].
In addition, the authors state that apolipoproteins and lipoproteins do not play a role in lipid transfer from the brain to the circulation. Several recent studies point to the existence of such a mechanism [ 5 ].
References:
1. Koudinov AR, Berezov TT, Koudinova NV. Alzheimer's amyloid beta and lipid metabolism: a missing link ? FASEB J. 1998; 12: 1097-1099 [ PubMed Citation ] [ Full text at FASEB J ]
2. O'Brien WT, et al. Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response. Integr.Physiol. Behav. Sci. 2000; 35: 120-31 [ PubMed Citation ]; Muldoon MF, et al. Effects of lovastatin on cognitive function and psychological well-being. Am. J. Med. 2000; 108: 538-46 [ PubMed Citation ].
3. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. published June 27, 2001, 10.1096/fj.00-0815fje [ PubMed Citation ] [ Abstract and Full text at FASEB J ] [ Authors WEB site ] [ Authors related letter at BMJ] [ another related letter at BMJ ]; Scanlon SM, Williams DC, Schloss P. Membrane cholesterol modulates serotonin transporter activity. Biochemistry 2001; 40: 10507-13 [ PubMed Citation ] [ Full text at Biochemistry ].
4. Koudinov AR, Koudinova NV. Neuronal Cholesterol Pathology is the Cause of Alzheimer's Disease. Soc. Neurosci. Abst. 2001; 27: 23.3 [ Abstract at ScholarOne.com ].
5. Shibata M, et al. Clearance of Alzheimer’s amyloid-b1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier. J. Clin. Invest. 2000; 106: 1489-99 [ PubMed Citation ] [ Abstract and Full text at JCI ]; Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer’s and normal aging CSF: implication for brain cholesterol pathology? Neurosci. Lett. 2001; In press.