Tuesday, February 8, 2011

Alzheimer’s Disease New Mechanism Regulating Cholesterol Levels in Brain Statin Dementia

Tags: Alzheimer's Cholesterol for Brain and Cells of Body Causes Early and Late Onset Medications Dementia Obesity Statin Side Effects Fructose

The holy grails of the study of Alzheimer’s Disease is to find the cause (s), detect it early, and develop an appropriate treatment. I suspect that all the medications that seniors take for a number of metabolic and other illnesses might be an additional cause of Alzheimer’s. The book “Our Daily Meds” by Melody Peterson lists a number of popular drugs that cause dementia. One bladder drug Detrol for incontinence does result in dementia. Also one antihistamine drug had to be taken off the market that I am aware of because it did not get rid of excess proteins. Recent work showed that the protein in excess, amyloid beta blocks our synapses neuron connections. Why is there excess protein?

Why do Alzheimer’s patients have moments of clarity? Simple it is a synaptic connection problem which various depending on how well the brain gets rid of excess protein or Amyloid Beta.

A close friend Joan in New Jersey called me a few years ago and asked me why the statin she was taking caused her normally sharp mind becoming sluggish. I told her that a number of people have reported that, but no explanation had been given. I told her that it is probably because the statins removed too much of the low density lipoprotein needed for the brain cells. She did not get back to me, but I assume she did what I suggested, take less Lipitor.

This is on the fly, but I will try to explain why Lipitor in excess can cause muscle degradation which can result in kidney failure due to an excess of myoglobin. Muscles are built up and degraded daily so they need cholesterol to rebuild the cells again. Without enough low density lipoproteins cholesterol, they start to degrade. This explanation could be already given, but so far I have not read about all the above explanations that I gave for the effect of Statins.

I started using Statins when my cholesterol went up to 300 after my kidney degradation and transplant from a malaria drug which also destroyed and degraded my kidney and liver. Yes, I became very yellow. But I did not know about this for a number of years. I went from a physically strong person who could ski all day and play three hours of tennis to one who stopped skiing and playing tennis. I went to many doctors, but since my creatinine was within normal limits they never suspected kidney disease. So much for diagnostic tests! Doctors can’t rely entirely on tests. They need to talk to patients in a non-threatening manner. My LDL is now in the sixties and I still take 10 mg of Lipitor every day now. My HDL is over 80 and the very important triglycerides are in the 60s.

Although my Internist and Nephrologist did not mention why I was first put on 10 mg of Lipitor every other day for one year, I figured out that when we have high levels of low density lipoproteins in the blood, the receptors for it recedes so it results in a sharp drop in the level of low density lipoproteins needed for the brain and cell walls of our body when we lower the levels of cholesterol in the blood. It is high because the body needs it and disease lowers the number of receptors. That may be why at least a few notice that they have trouble thinking. For others it does not matter.

I recommended taking it every other day initially and later daily because the important function of statins is to reduce the amount of fresh plaque which cause heart attacks and strokes. The clever Swedes found by tracer studies that it is the fresh plaque and not the hardened plaque that is the problem. Busy Americans were slow to pick this up and still seem to ignore the very low density lipoprotein link to early and late onset Alzheimer’s Disease.

The brain weighs 2 percent of our body but it uses 20 percent of all the cholesterol made by the liver mainly. Statins reduces the liver’s production of cholesterol. The brain also metabolizes the most glucose, not our muscles.

… “The gene, which is called brain-derived neurotrophic factor (BDNF), is crucial to maintaining healthy function of the brain, primarily the brain's memory centre of the hippocampus and (adjacent pathway) entorhinal cortex, and is responsible for learning and memory function. Past research has found that less BDNF is present in the memory centre of those diagnosed with Alzheimer's disease. However genetic association studies alone have not produced definite findings regarding this gene. Instead, a combination of genetics and brain imaging were used to demonstrate clear effects of this gene in the brain.

In the study published in the Archives of General Psychiatry, a variation of the BDNF gene called val66met, was tracked and examined in healthy individuals to see what effect it had on the brain. Genotyping was used to determine which study participants carried the gene variation.

Then two types of brain imaging -- high-resolution magnetic resonance imaging (MRI) cortical thickness mapping and diffusion tensor imaging (DTI) (an MRI-based technique that measures key structural connections in the brain)-- were applied to measure the physical structures of the brain in each individual. This combination of genetic screening and imaging found that BDNF val66met gene variation influenced exactly those brain structures and connections that deteriorate at the earliest phases of Alzheimer's disease.

"Our sample consisted of healthy adults who passed all cognitive testing and displayed no clinical symptoms of Alzheimer's disease, yet the brains of those who carried the gene variation had differences in their brain structures consistent with changes we see in people at the earliest stages of Alzheimer's disease," said Dr. Aristotle Voineskos, physician and scientist at CAMH, and principal investigator of the study. … “ http://www.sciencedaily.com/releases/2011/02/110208093254.htm

While reading the latest theory on the Cause of Late Onset Alzheimer’s Aristotle Voineskos excerpted above, I noticed a related study below that makes more provable sense, a theory that I subscribed to for a while based on Alzheimer’s mice study which showed that initially it is not the plaque but the synaptic connection interference which caused the thinking problem. Once enzymes were used to get rid of the excess proteins, the old mice behaved just like the young mice in going through the maze.

I believe the study below by a non-Ivy League school shows me the true cause of Alzheimer’s. Remember genetic causes are very low while late onset Alzheimer’s accounts for 95% of the this disease.

Also remember that obesity and late onset Alzheimer’s are strongly correlated which is consistent with the cholesterol mechanism by the author below.

Since 1985 when Reagan subsidized the cost of corn to such a large amount that sugar from corn could be economically chemically converted to a mixture of fructose and glucose and started selling it without testing and was partially hydrogenated oils resulting in large amounts of deadly trans fats.

Our bodies evolved when we did not have an abundance of sweet fruit so eating or taking any one food or supplement in excess may make it for our body to cope with metabolizing it. Our liver metabolizes fructose and a large part of it goes to very low density lipoproteins which eventually lead to Alzheimer's Disease. Both excess cane sugar and High Fructose Corn Syrup works the same way as alcohol does in the liver. It causes cirrhosis. It can also cross-link our DNA. What did the cave humans eat? What can we eat? Everything except processed foods with preservatives and other junk. Do you take a large amount anti-oxidant supplements? Do you know that our metabolic processes depend on free radicals to function? Too much of anything is bad for you. Even water!

Jim Kawakami, Jan 8, 2011, http://jimboguy.blogspot.com

Cholesterol Metabolism Links Early and Late Onset Alzheimer’s Disease, Guojun Bu, Professor of Pediatrics and Cell Biology and Physiology. ScienceDaily (Oct. 9, 2007) — http://www.sciencedaily.com/releases/2007/10/071004134105.htm Although the causes of Alzheimer's disease are not completely understood, amyloid-beta (A-beta) is widely considered a likely culprit -- the "sticky" protein clumps into plaques thought to harm brain cells.

But now researchers at Washington University School of Medicine in St. Louis have uncovered evidence strengthening the case for another potential cause of Alzheimer's. The finding also represents the first time scientists have found a connection between early- and late-onset Alzheimer's.

In a study published in the journal Neuron, the scientists report that when A-beta is made, a small bit of protein is also released that can regulate cholesterol levels in the brain. The discovery adds weight to the less prominent theory that abnormal brain cholesterol metabolism plays a role in the mental decline seen in Alzheimer's patients.

"Our research links two major determinants for early- and late-onset Alzheimer's disease," says senior author Guojun Bu, Ph.D., professor of pediatrics and of cell biology and physiology. "And we've shown that the process that links them is implicated in brain cholesterol metabolism."

The report follows closely on another study reporting that statins, widely prescribed cholesterol-lowering drugs, could prevent certain neural changes that signal the progression of Alzheimer's disease. Additional earlier studies support the idea that statins could benefit Alzheimer's patients; however, other studies have found no such protective effect from statins.

"The studies of statins and Alzheimer's have generated quite a bit of controversy," Bu says. "Those that show positive effects from statins seem to suggest that high cholesterol could increase the risk of Alzheimer's disease. But other evidence contradicts this idea."

In fact, the brain needs a high level of cholesterol, according to Bu. "The brain represents only about 2 percent of your body weight, but actually has about 20 percent of your body's cholesterol," Bu says. "There is strong evidence that cholesterol is important for synaptic function and is an essential component of cell membranes in the brain, and I believe partial defects in the regulation of cholesterol metabolism in the brain likely contribute to the development of Alzheimer's."

In the current study, Bu and colleagues found an aspect of cholesterol transport and metabolism in the brain was a link between early- and late-onset Alzheimer's disease. Both forms of the disease result in similar brain lesions and have the same symptoms, including difficulties communicating, learning, thinking and reasoning, which suggests they share underlying mechanisms. But until now, no one has been able to identify such a mechanism.

Early-onset Alzheimer's can be traced to mutations in one of three genes, and the gene coding for A-beta's precursor, APP, is one of these. People with mutations in APP nearly always develop Alzheimer's disease, usually at a relatively young age.

The genetic origins of late-onset Alzheimer's, which accounts for 95 percent of cases, have proven harder to pin down. However, studies have shown that people who have a particular mutation in the gene for a cholesterol carrier called apolipoprotein E are far more likely to develop Alzheimer's in old age than those who don't have the mutation.

Bu and colleagues demonstrated that APP and apolipoprotein E have a molecular connection. When APP is cleaved by a specific enzyme in the brain, it releases A-beta plus a small protein fragment. The fragment then can regulate apolipoprotein E, which moves cholesterol in the brain from support cells to neurons.

Past research by others implies that neural synapses, the junctions that nerves use to send impulses and communicate, are particularly sensitive to cholesterol levels and that interfering with cholesterol transport and metabolism could cause loss of synapses and degeneration of nerves.

"Cholesterol metabolism in the brain is an understudied area, and our findings could inspire Alzheimer's researchers to look further into the role of the cholesterol pathway," Bu says. "Right now, research on Alzheimer's treatment focuses largely on reducing A-beta production or increasing its clearance from the brain. Our study suggests that there could be an alternate way to treat the disease, perhaps by modulating the function of apolipoprotein E and cholesterol in the brain."

Bu and his colleagues plan to screen for compounds that regulate the molecular components that they found to be involved in cholesterol metabolism. They hypothesize that such compounds could work to enhance the brain's cholesterol metabolism and alleviate Alzheimer's symptoms.

Reference: Liu Q, Zerbinatti CV, Zhang J, Hoe H-S, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron Oct. 4, 2007.

Funding from the National Institutes of Health, the Alzheimer's Association and the American Health Assistance Foundation supported this research.

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