Animal Pharm: Ancient Transporters: HDL and LDL Lipoproteins Carry Precious Cargo
We each individually and uniquely have widely varied lipoprotein patterns (LDL, TG, HDL) determined by our genetics, the microniche our ancestors evolved and survived in, and our apolipoprotein E. Apo E is mainly found in HDL and LDL particles but also free form in the circulation as well. It aids lipoprotein particles in docking up to cell membranes to unload contents into a destination cell or the liver.
Apo E determines the LDL-quantity. Three alleles for apoE exist and we each have 2 copies from a mix from our parents - E2, E3 or E4. ApoE to me is like a special key to unlock troubled doors. Those with E4 alleles have lipoproteins with the least apoE (perhaps true H-G, more cholesterol hung out longer in circulation). Geographically the incidence of E4 rises toward a northern distribution in Europe, away from the equator. Those with E2, more apoE (perhaps more agarian adapted). Energy flux patterns and metabolism are mildly different: E4, more carbohydrate sensitive; E2, less.
Many 'cardiac' rat models use apoE-deficient mice because these animals inevitably develop horrific plaque and atherosclerotic disease and blocked arteries, on high carb rat chow.
The lower the apo E alleles, the lower the total cholesterol [ref 2]. The researchers (above) demonstrate the LDL and HDL trend in parallel with total cholesterol and the higher the E. Conversely, triglycerides grow higher, the lower the apo E.
It seems finally that the medical community be viewing the true science and questioning the BS. If LDL is genetically determined by the apoE type and is a false coronary risk factor, then what is the true cause of coronary events, MIs, angina and plaque destabilization?
Naturally if one is apoE 4/4 (rare), then one is likely to have the highest LDL amongst friends and aquaintances. Is it harmful? Depends. ApoE 4/4 are more likely to be HIGHLY insulin resistant, inflamed and carbohydrate sensitive. In the modern industrial environment where whole food, ancestrally-inclined meals are endangered species... perhaps.
Are apoE 4/4 the true survivors of Earth? They are less likely to suffer from infections or starvation which were the major reasons for mortality outside of predation prior to neolithic times. Add to that vascular protection from Lp(a) from vitamin C-deficiency hemolysis and one has a winning combination for longevity given the right circumstances when inflammation is well regulated and gene-protein expression optimal.
The higher the LDL, the higher the Lp(a), the better survival?
Wednesday, 29 May 2013
Sunday, 26 May 2013
APOE4 and medium chain triglycerides - Coconut Oil, Ketones and Alzheimer's:
APOE4 and medium chain triglycerides - Coconut Oil, Ketones and Alzheimer's:
Friday, June 19, 2009
Friday, June 19, 2009
APOE4 and medium chain triglycerides
Due to results of studies done by Accera in developing Axona, there is a possible misconception that the medium chain triglycerides will not help people with AD who are APOE4.
Axona has only one of the medium chain triglycerides (C:8) but coconut oil has C:6, C:8, C:10, C:12 (all medium chain triglycerides) and five other fatty acids, including some monounsaturated and polyunsaturated fatty acids, including the essential fatty acid omega-6 (but no omega-3, which is necessary and should be supplemented.) It also happens to have some phytosterol, which is one of the substances that lowers cholesterol and is the basic component in some of the cholesterol lowering agents! It is very possible that each of the fatty acids in coconut oil plays an important and different role in the metabolism of our brains and other organs.
Another possibility is that the Axona folks did not have a huge number of people in their trials and I often wonder if the APOE4 problem was a fluke in their study.
Also, some people in their studies had "mild cognitive impairment," not yet diagnosed with A.D. Dr. Richard Veech of the NIH, an expert in ketones who makes a ketone ester, says that he can think of no biochemical reason why Axona wouldn't work for someone with APOE4.
Steve is APOE4 and responded very well to the medium chain fatty acids. I also read this before trying this with Steve, and therefore expected that MCT oil would not do much for him. I decided to try it anyway in the form of coconut oil for Steve and the rest is history of the happiest kind.
posted by Dr. Mary Newport at 9:04 AM
Monday, 8 April 2013
ApoE Genotyping: The Test
ApoE Genotyping: The Test
Also known as: ApoE cardiac risk; ApoE 2 mutations; APOE4 genotype
Formal name: Apolipoprotein E genotyping
Related tests:
Cardiac Risk Assessment; HDL Cholesterol; LDL Cholesterol; Lipid Profile; Triglycerides; Tau/Aß42
Cardiac Risk Assessment; HDL Cholesterol; LDL Cholesterol; Lipid Profile; Triglycerides; Tau/Aß42
The Test
How is it used?
In Cardiovascular Disease (CVD)
The test for ApoE is not widely used and it's clinical usefulness is still being researched. When it is ordered, it may be used in combination with other lipid tests that evaluate risk for CVD, such as cholesterol levels and lipoprotein electrophoresis. It may sometimes be used to check for and help diagnose a genetic component to a lipid abnormality.
Testing for ApoE may sometimes be ordered to help guide lipid treatment. In cases of high cholesterol and triglyceride levels, statins are usually considered the treatment of choice to decrease the risk of developing CVD. However, there is a wide variability in the response to these lipid-lowering drugs that is in part influenced by the Apo E genotype.
Though appropriately responsive to a low fat diet, people with ApoE e4 may be less likely than those with ApoE e2 to respond to statins by decreasing their levels of LDL-C and may require adjustments to their treatment plans. At present, the clinical utility of this type of information is yet to be totally understood. Dietary adjustment and statin drugs are the preferred agents for lipid-lowering therapy. Apo E genotyping may be used to provide supplemental information.
ApoE testing may also be ordered occasionally to help diagnose type III hyperlipoproteinemia in a person with symptoms that suggest the disorder and to evaluate the potential for the condition in other family members.
In Alzheimer's Disease
ApoE genotyping is also sometimes used as an adjunct test to help in the diagnosis of probable late onset Alzheimer's disease (AD) in symptomatic adults. It is called susceptibility or risk factor testing because it indicates whether there is an increased risk of AD but is not specifically diagnostic of AD. If a patient has dementia, the presence of ApoE4 may increase the likelihood that the dementia is due to AD, but does not prove that it is. There are no clear-cut tests to diagnose Alzheimer's disease during life. Physicians can, however, make a reasonably accurate clinical diagnosis of AD by ruling out other potential causes of dementia and checking for a genetic predisposition to AD with ApoE genotyping as supplemental information in conjunction with Tau/Aß42 testing.
The test for ApoE is not widely used and it's clinical usefulness is still being researched. When it is ordered, it may be used in combination with other lipid tests that evaluate risk for CVD, such as cholesterol levels and lipoprotein electrophoresis. It may sometimes be used to check for and help diagnose a genetic component to a lipid abnormality.
Testing for ApoE may sometimes be ordered to help guide lipid treatment. In cases of high cholesterol and triglyceride levels, statins are usually considered the treatment of choice to decrease the risk of developing CVD. However, there is a wide variability in the response to these lipid-lowering drugs that is in part influenced by the Apo E genotype.
Though appropriately responsive to a low fat diet, people with ApoE e4 may be less likely than those with ApoE e2 to respond to statins by decreasing their levels of LDL-C and may require adjustments to their treatment plans. At present, the clinical utility of this type of information is yet to be totally understood. Dietary adjustment and statin drugs are the preferred agents for lipid-lowering therapy. Apo E genotyping may be used to provide supplemental information.
ApoE testing may also be ordered occasionally to help diagnose type III hyperlipoproteinemia in a person with symptoms that suggest the disorder and to evaluate the potential for the condition in other family members.
In Alzheimer's Disease
ApoE genotyping is also sometimes used as an adjunct test to help in the diagnosis of probable late onset Alzheimer's disease (AD) in symptomatic adults. It is called susceptibility or risk factor testing because it indicates whether there is an increased risk of AD but is not specifically diagnostic of AD. If a patient has dementia, the presence of ApoE4 may increase the likelihood that the dementia is due to AD, but does not prove that it is. There are no clear-cut tests to diagnose Alzheimer's disease during life. Physicians can, however, make a reasonably accurate clinical diagnosis of AD by ruling out other potential causes of dementia and checking for a genetic predisposition to AD with ApoE genotyping as supplemental information in conjunction with Tau/Aß42 testing.
When is it ordered?
- ApoE genotyping is sometimes ordered when a patient has significantly elevated cholesterol and triglyceride levels that do not respond to dietary and exercise lifestyle changes.
- When family members have ApoE e2/e2 and a doctor wants to see if the person might be at a higher risk for early heart disease.
- When someone has yellowish skin lesions called xanthomas and the doctor suspects Type III hyperlipoproteinemia.
What does the test result mean?
People with ApoE e2/e2 alleles
are at a higher risk of premature vascular disease, but they may never
develop disease. Likewise, they may have the disease and not have
e2/e2 alleles because it is only one of the factors involved. ApoE
genotyping adds additional information and, if symptoms are present,
e2/e2 can help confirm type III hyperlipoproteinemia.
Those who have ApoE e4/e4 are more likely to have atherosclerosis. People who have symptoms of late onset Alzheimer's disease (AD) AND have one or more ApoE e4 copies of the e4 gene are more likely to have AD. However, it is not diagnostic of AD and should NOT be used to screen asymptomatic people or their family members. Many of those who have e4 alleles will never develop AD. Even in symptomatic people, only about 60% of those with late onset AD will have ApoE e4 alleles.
ApoE e3 has "normal" lipid metabolism, thus may not have any genotype impact.
Those who have ApoE e4/e4 are more likely to have atherosclerosis. People who have symptoms of late onset Alzheimer's disease (AD) AND have one or more ApoE e4 copies of the e4 gene are more likely to have AD. However, it is not diagnostic of AD and should NOT be used to screen asymptomatic people or their family members. Many of those who have e4 alleles will never develop AD. Even in symptomatic people, only about 60% of those with late onset AD will have ApoE e4 alleles.
ApoE e3 has "normal" lipid metabolism, thus may not have any genotype impact.
Is there anything else I should know?
Although
ApoE genotyping is being used clinically by Alzheimer's experts, the
most it can provide at this time is additional information about a
patient with dementia. A definite diagnosis of Alzheimer's disease can only be made by examining a patient's brain tissue after their death.
ApoE genotyping is not available in every laboratory. If your doctor recommends this test, your specimen will need to be sent to a reference lab, and results may take longer to return than they would from a local laboratory.
Alterations in lipid concentrations do not lead directly to vascular disease or atherosclerosis. Other factors, such as obesity, diabetes, and hypothyroidism, also play a role in whether a person actually develops disease.
ApoE genotyping is not available in every laboratory. If your doctor recommends this test, your specimen will need to be sent to a reference lab, and results may take longer to return than they would from a local laboratory.
Alterations in lipid concentrations do not lead directly to vascular disease or atherosclerosis. Other factors, such as obesity, diabetes, and hypothyroidism, also play a role in whether a person actually develops disease.
ApoE4 - The Ancestral Allele | For ApoE4 carriers interested in primal diets and science
ApoE4 - The Ancestral Allele | For ApoE4 carriers interested in primal diets and science
Googling for the rate of APOE4 among Native Americans, I found this paper on omega-3 fats and ApoE4:
The important thing for us is the dietary recommendations. Some highlights:
Another important point the paper makes is that while O3s provide many benefits, they are also vulnerable to oxidative damage. Depending on the body’s redox state, O3s can be neurotrophic (good for the brain) or neurotoxic (not so good).
The paper seems to conflate a low fat diet with a plant-centered, unprocessed one. While it has some great information on omega-3s, it doesn’t have much to answer other key primal / e4 fat questions like whether saturated fats are good (as in primal) or bad (because of differences in lipid metabolism for e4s).
Googling for the rate of APOE4 among Native Americans, I found this paper on omega-3 fats and ApoE4:
The most recent statistics indicate that dietary intake of omega-3 PUFA is insufficient in >95% of Americans.
Deficits in omega-3s have been shown to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in all cause dementia, including Alzheimer’s disease.
DHA (22:6[n-3]), specifically, is a critical contributor to cell structure and function in the nervous system, and a recently identified DHA-derived messenger, neuroprotecting D1 (NPD1) has been found to regulate brain cell survival and to promote non-amyloidogenic processing of amyloid precursor protein, thus protecting against Alzheimer’s disease by inhibiting formation of β-amyloid.
Studies utilizing omega-3 supplementation to improve cognitive function in elders, however, have had mixed outcomes, an inconsistency which newly published research indicates is related to ApoE genotype. ApoE ε4 carriers have not been able to benefit from omega-3s. This article discusses why and what can be done to enable carriers of the ApoeE ε4 allele to receive the neuroprotective benefits of omega-3s.
The important thing for us is the dietary recommendations. Some highlights:
ApoE ε4 carriers are the canaries in the mine of the Western way of life.
Individuals with this genetic heritage cannot afford the “normal” level of dietary and lifestyle insults typical of life in the modern industrialized world because the ApoE ε4 allele magnifies the risks inherent in the Western diet and lifestyle.
…
Despite the disproportionately high prevalence of ApoE ε4, cardiovascular disease and diabetes among Native Americans, and the Pima Indians, specifically, research examining a Native American rural population in nearby New Mexico clearly shows that carrying the ApoE ε4 allele does not increase the risk for any of these conditions in people eating a low fat diet and following an active lifestyle.
Another important point the paper makes is that while O3s provide many benefits, they are also vulnerable to oxidative damage. Depending on the body’s redox state, O3s can be neurotrophic (good for the brain) or neurotoxic (not so good).
The paper seems to conflate a low fat diet with a plant-centered, unprocessed one. While it has some great information on omega-3s, it doesn’t have much to answer other key primal / e4 fat questions like whether saturated fats are good (as in primal) or bad (because of differences in lipid metabolism for e4s).
ApoE and HDL, and heart and cerebrovascular disease: LDL-apheresis therapy
Association of ApoE and HDL-C with cardiovascular and cerebrovascular disease:
potential benefits of LDL-apheresis therapy,
Clinical Lipidology, Future Medicine
June 2009, Vol. 4, No. 3, Pages 311-329 , DOI 10.2217/clp.09.21
Review
Patrick M Moriarty
ApoE forms a lipid–protein complex with HDL-cholesterols (HDL-C) and remnant lipoproteins and is an important regulator of cholesterol and lipid clearance, transport and distribution. In the CNS, ApoE is strictly bound to HDL.
Unlike ApoE2 or ApoE3, the ApoE4 isoform is associated with both coronary artery disease and Alzheimer’s disease.
HDL-C levels may possess a U-shaped association with vascular diseases and HDL-C size might reflect an alteration in function.
Inflammation plays a key role in coronary artery disease and Alzheimer’s disease.
Elevated inflammatory markers such as C-reactive protein and serum amyloid A are associated with both diseases. Serum amyloid A, similar to ApoE, binds to HDL-C and may alter the lipoproteins size and function.
Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated plasma levels of LDL-cholesterol (LDL-C), xanthomas and premature coronary artery disease. FH patient’s plasma contains decreased levels of HDL-C with increased levels of ApoE4 and ApoE-bound HDL.
LDL-apheresis therapy lowers LDL-C and is designated for FH patients resistant to pharmacotherapy.
LDL-apheresis also lowers inflammatory HDL-C, ApoE4, and a host of inflammatory markers such as C-reactive protein and serum amyloid A. LDL-apheresis, adjunct to reducing cholesterol, may provide additional benefit to patients with cardiovascular and cerebrovascular diseases.
potential benefits of LDL-apheresis therapy,
Clinical Lipidology, Future Medicine
June 2009, Vol. 4, No. 3, Pages 311-329 , DOI 10.2217/clp.09.21
Review
Association of ApoE and HDL-C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy
ApoE forms a lipid–protein complex with HDL-cholesterols (HDL-C) and remnant lipoproteins and is an important regulator of cholesterol and lipid clearance, transport and distribution. In the CNS, ApoE is strictly bound to HDL.
Unlike ApoE2 or ApoE3, the ApoE4 isoform is associated with both coronary artery disease and Alzheimer’s disease.
HDL-C levels may possess a U-shaped association with vascular diseases and HDL-C size might reflect an alteration in function.
Inflammation plays a key role in coronary artery disease and Alzheimer’s disease.
Elevated inflammatory markers such as C-reactive protein and serum amyloid A are associated with both diseases. Serum amyloid A, similar to ApoE, binds to HDL-C and may alter the lipoproteins size and function.
Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated plasma levels of LDL-cholesterol (LDL-C), xanthomas and premature coronary artery disease. FH patient’s plasma contains decreased levels of HDL-C with increased levels of ApoE4 and ApoE-bound HDL.
LDL-apheresis therapy lowers LDL-C and is designated for FH patients resistant to pharmacotherapy.
LDL-apheresis also lowers inflammatory HDL-C, ApoE4, and a host of inflammatory markers such as C-reactive protein and serum amyloid A. LDL-apheresis, adjunct to reducing cholesterol, may provide additional benefit to patients with cardiovascular and cerebrovascular diseases.
| Full Text | PDF (2053 KB) | PDF Plus (2177 KB) |
HDL, apoE4 and Alzheimer’s Disease » Alzheimer's Association | Blog
HDL Cholesterol and Alzheimer’s Disease » Alzheimer's Association | Blog
According to researchers at Columbia University, people with high levels of HDL cholesterol (the “good” form) are 60 percent less likely to develop AD.
The researchers followed 1,130 seniors with no history of memory loss or dementia and measured their cholesterol levels every 18 months for four years. When the researchers compared the cholesterol levels of study participants with and without Alzheimer’s, they found that those with the highest HDL counts, greater than 55 mg/dL, had about a 60 percent reduced risk of developing the disease compared to those whose levels were less than 39 mg/dL.
Their findings support the theory that high levels of HDL cholesterol are correlated with lower incidence of AD. The study was published earlier this week in the Archives of Neurology and sheds more light on the interactions between cholesterol and AD.
Apolipoprotein E (apoE), as readers of this blog will recall, participates in the mobilization and distribution of cholesterol among various tissues of the body, including the brain. In humans, there are three common isoforms of apoE: apoE2, apoE3 and apoE4.
ApoE4 differs from apoE3, the most common isoform of apoE. A single e4 allele is sufficient to increase the risk of developing atherosclerosis, and also Alzheimer’s disease.
The e4 allele results in slightly elevated plasma LDL cholesterol levels and a small but significant decrease in plasma HDL levels. HDL is one of the major carriers of protein in and out of the brain, and also binds to beta-amyloid.
This finding further advances the idea that the interplay between cholesterol, cholesterol-carrying proteins such as apoE and HDL, and beta-amyloid may be critical in the development of Alzheimer’s disease.
This study has important strengths. It is a prospective cohort study designed for the diagnosis of cognitive decline that has complete clinical and neuropsychological evaluation at each interval.
Guidelines recommend that men raise HDL levels that are less than 40 mg/dL and that women increase HDL numbers less 50 mg/dL. An HDL of 60 mg/dL or higher is optimal.
Michael S. Rafii, M.D., Ph.D.
Associate Medical Director, ADCS Medical Core
This post originally appeared in Alzheimer’s Insights, an ADCS Blog.
* Association of Higher Levels of High-Density Lipoprotein Cholesterol in Elderly Individuals and Lower Risk of Late-Onset Alzheimer Disease. Christiane Reitz et al., Arch Neurol. 2010;67(12):1491-1497.
"This finding further advances the idea that the interplay between cholesterol, cholesterol-carrying proteins such as apoE and HDL, and beta-amyloid may be critical in the development of Alzheimer’s disease. "HDL, apoE4 and Alzheimer’s Disease » Alzheimer's Association | Blog
According to researchers at Columbia University, people with high levels of HDL cholesterol (the “good” form) are 60 percent less likely to develop AD.
The researchers followed 1,130 seniors with no history of memory loss or dementia and measured their cholesterol levels every 18 months for four years. When the researchers compared the cholesterol levels of study participants with and without Alzheimer’s, they found that those with the highest HDL counts, greater than 55 mg/dL, had about a 60 percent reduced risk of developing the disease compared to those whose levels were less than 39 mg/dL.
Their findings support the theory that high levels of HDL cholesterol are correlated with lower incidence of AD. The study was published earlier this week in the Archives of Neurology and sheds more light on the interactions between cholesterol and AD.
Apolipoprotein E (apoE), as readers of this blog will recall, participates in the mobilization and distribution of cholesterol among various tissues of the body, including the brain. In humans, there are three common isoforms of apoE: apoE2, apoE3 and apoE4.
ApoE4 differs from apoE3, the most common isoform of apoE. A single e4 allele is sufficient to increase the risk of developing atherosclerosis, and also Alzheimer’s disease.
The e4 allele results in slightly elevated plasma LDL cholesterol levels and a small but significant decrease in plasma HDL levels. HDL is one of the major carriers of protein in and out of the brain, and also binds to beta-amyloid.
This finding further advances the idea that the interplay between cholesterol, cholesterol-carrying proteins such as apoE and HDL, and beta-amyloid may be critical in the development of Alzheimer’s disease.
This study has important strengths. It is a prospective cohort study designed for the diagnosis of cognitive decline that has complete clinical and neuropsychological evaluation at each interval.
Guidelines recommend that men raise HDL levels that are less than 40 mg/dL and that women increase HDL numbers less 50 mg/dL. An HDL of 60 mg/dL or higher is optimal.
Michael S. Rafii, M.D., Ph.D.
Associate Medical Director, ADCS Medical Core
This post originally appeared in Alzheimer’s Insights, an ADCS Blog.
* Association of Higher Levels of High-Density Lipoprotein Cholesterol in Elderly Individuals and Lower Risk of Late-Onset Alzheimer Disease. Christiane Reitz et al., Arch Neurol. 2010;67(12):1491-1497.
Saturday, 6 April 2013
Alzheimer's Disease Genetics Fact Sheet | National Institute on Aging
Alzheimer's Disease Genetics Fact Sheet | National Institute on Aging
Scientists don't yet fully understand what causes Alzheimer's disease. However, the more they learn about this devastating disease, the more they realize that genes* play an important role in its development. Research conducted and funded by the National Institute on Aging (NIA) at the National Institutes of Health and others is advancing the field of Alzheimer's disease genetics.
*Terms in bold are defined at the end of this fact sheet.
In other diseases, a genetic variant may occur. This change in a gene can sometimes cause a disease directly. More often, it acts to increase or decrease a person's risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.
Familial Alzheimer's disease is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.
Scientists know that each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet known. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease. A child whose mother or father carries a genetic mutation for FAD has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child almost surely will develop FAD.
Critical research findings about early-onset Alzheimer's have helped identify key steps in the formation of brain abnormalities typical of Alzheimer's disease. They have also led to the development of imaging tests that show the accumulation of amyloid in the living brain. In addition, the study of Alzheimer's genetics has helped explain some of the variation in the age at which the disease develops.
NIA-supported scientists are continuing this research through the Dominantly Inherited Alzheimer Network (DIAN), an international partnership to study families with a genetic mutation that causes early-onset Alzheimer's disease. By observing the biological changes that occur in these families long before symptoms appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms. In addition, scientists are attempting to develop tests that will enable diagnosis of Alzheimer's before clinical signs and symptoms appear, as it is likely that early treatment will be critical as therapies become available.
The single-gene mutations directly responsible for early-onset Alzheimer's disease do not seem to be involved in late-onset Alzheimer's. Researchers have not found a specific gene that causes the late-onset form of the disease. However, one genetic risk factor does appear to increase a person's risk of developing the disease. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in several different forms, or alleles. Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with one or two APOE ε4 alleles never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.
Using a relatively new approach called genome-wide association study (GWAS), researchers have identified a number of genes in addition to APOE ε4 that may increase a person's risk for late-onset Alzheimer's, including BIN1, CLU, PICALM, and CR1. Finding genetic risk factors like these helps scientists better understand how Alzheimer's disease develops and identify possible treatments to study.
At present, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer's. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that APOE testing is useful for studying Alzheimer's disease risk in large groups of people but not for determining any one person's specific risk.
In doctors' offices and other clinical settings, genetic testing is used for people with a family history of early-onset Alzheimer's disease. However, it is not generally recommended for people at risk of late-onset Alzheimer's.
P.O. Box 8250
Silver Spring, MD 20907-8250
1-800-438-4380 (toll-free)
www.nia.nih.gov/alzheimers
The National Institute on Aging's ADEAR Center offers information and publications for families, caregivers, and professionals on diagnosis, treatment, patient care, caregiver needs, long-term care, education and training, and research related to Alzheimer's disease. Staff members answer telephone, email, and written requests and make referrals to local and national resources. The ADEAR website provides free, online publications in English and Spanish; email alerts; a clinical trials database; the Alzheimer's Disease Library database; and more.
Additional information about genetics in health and disease is available from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Visit the NHGRI website at www.genome.gov.
The National Library of Medicine's National Center for Biotechnology Information also provides genetics information at www.ncbi.nlm.nih.gov.
Alzheimer's Association
225 North Michigan Avenue
Floor 17
Chicago, IL 60601-7633
1-800-272-3900 (toll-free)
1-866-403-3073 (TTY/toll-free)
www.alz.org
Alzheimer's Foundation of America
322 Eighth Avenue, 7th floor
New York, NY 10001
1-866-232-8484 (toll-free)
www.alzfdn.org
A Service of the National Institute on Aging
National Institutes of Health
U.S. Department of Health and Human Services
Scientists don't yet fully understand what causes Alzheimer's disease. However, the more they learn about this devastating disease, the more they realize that genes* play an important role in its development. Research conducted and funded by the National Institute on Aging (NIA) at the National Institutes of Health and others is advancing the field of Alzheimer's disease genetics.
*Terms in bold are defined at the end of this fact sheet.
The Genetics of Disease
Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. If a person inherits from a parent a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer's disease are examples of inherited genetic disorders.In other diseases, a genetic variant may occur. This change in a gene can sometimes cause a disease directly. More often, it acts to increase or decrease a person's risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.
Alzheimer’s Disease Genetics
Alzheimer's disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary tangles, the loss of connections between nerve cells, or neurons, in the brain, and the death of these nerve cells. There are two types of Alzheimer's—early-onset and late-onset. Both types have a genetic component.DNA, Chromosomes, and Genes
Each chromosome contains many thousands of segments, called genes. People inherit two copies of each gene from their parents, except for genes on the X and Y chromosomes, which, among other functions, determine a person's sex. The genes “instruct” the cell to make unique proteins that, in turn, dictate the types of cells made. Genes also direct almost every aspect of the cell's construction, operation, and repair. Even slight changes in a gene can produce a protein that functions abnormally, which may lead to disease. Other changes in genes may increase or decrease a person's risk of developing a particular disease. |
Early-Onset Alzheimer's Disease
Early-onset Alzheimer's disease occurs in people age 30 to 60. It is rare, representing less than 5 percent of all people who have Alzheimer's. Some cases of early-onset Alzheimer's have no known cause, but most cases are inherited, a type known as familial Alzheimer's disease (FAD).Familial Alzheimer's disease is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.
Scientists know that each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet known. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease. A child whose mother or father carries a genetic mutation for FAD has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child almost surely will develop FAD.
Critical research findings about early-onset Alzheimer's have helped identify key steps in the formation of brain abnormalities typical of Alzheimer's disease. They have also led to the development of imaging tests that show the accumulation of amyloid in the living brain. In addition, the study of Alzheimer's genetics has helped explain some of the variation in the age at which the disease develops.
NIA-supported scientists are continuing this research through the Dominantly Inherited Alzheimer Network (DIAN), an international partnership to study families with a genetic mutation that causes early-onset Alzheimer's disease. By observing the biological changes that occur in these families long before symptoms appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms. In addition, scientists are attempting to develop tests that will enable diagnosis of Alzheimer's before clinical signs and symptoms appear, as it is likely that early treatment will be critical as therapies become available.
Late-Onset Alzheimer's Disease
Most cases of Alzheimer's are the late-onset form, which develops after age 60. The causes of late-onset Alzheimer's are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that influence a person's risk for developing the disease.The single-gene mutations directly responsible for early-onset Alzheimer's disease do not seem to be involved in late-onset Alzheimer's. Researchers have not found a specific gene that causes the late-onset form of the disease. However, one genetic risk factor does appear to increase a person's risk of developing the disease. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in several different forms, or alleles. Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
- APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.
- APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
- APOE ε4 is present in about 25 to 30 percent of the population and in about 40 percent of all people with late-onset Alzheimer's. People who develop Alzheimer's are more likely to have an APOE ε4 allele than people who do not develop the disease.
APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with one or two APOE ε4 alleles never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.
Using a relatively new approach called genome-wide association study (GWAS), researchers have identified a number of genes in addition to APOE ε4 that may increase a person's risk for late-onset Alzheimer's, including BIN1, CLU, PICALM, and CR1. Finding genetic risk factors like these helps scientists better understand how Alzheimer's disease develops and identify possible treatments to study.
Genetic Testing
Although a blood test can identify which APOE alleles a person has, it cannot predict who will or will not develop Alzheimer's disease. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy because too many other factors may influence its development and progression.At present, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer's. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that APOE testing is useful for studying Alzheimer's disease risk in large groups of people but not for determining any one person's specific risk.
In doctors' offices and other clinical settings, genetic testing is used for people with a family history of early-onset Alzheimer's disease. However, it is not generally recommended for people at risk of late-onset Alzheimer's.
Epigenetics: Nature Meets NurtureScientists have long thought that genetic and environmental factors interact to influence a person's biological makeup, including the predisposition to different diseases. More recently, they have discovered the biological mechanisms for those interactions. The expression of genes (when particular genes are “switched” on or off) can be affected—positively and negatively—by environmental factors, such as exercise, diet, chemicals, or smoking, to which an individual may be exposed, even in the womb.Epigenetics is an emerging frontier of science focused on how and when particular genes are expressed. Diet and exposure to chemicals in the environment, among other factors, throughout all stages of life can alter a cell's DNA in ways that affect the activity of genes. That can make people more or less susceptible to developing a disease later in life. There is some emerging evidence that epigenetic mechanisms contribute to Alzheimer's disease. Epigenetic changes, whether protective, benign, or harmful, may help explain, for example, why one family member develops the disease and another does not. Research supported by the National Institutes of Health continues to explore this avenue.
The epigenome can “mark” DNA in two ways, both of which play a role in turning genes off or on. The first occurs when certain chemical tags called methyl groups attach to the backbone of a DNA molecule. The second occurs when a variety of chemical tags attach to the tails of histones, which are spool-like proteins that package DNA neatly into chromosomes. This action affects how tightly DNA is wound around the histones. |
Research Questions
Discovering all that we can about the role of Alzheimer's disease risk-factor genes is an important area of research. Understanding more about the genetic basis of the disease will help researchers:- Answer a number of basic questions—What makes the disease process begin? Why do some people with memory and other thinking problems develop Alzheimer's while others do not?
- Determine how risk-factor genes may interact with other genes and lifestyle or environmental factors to affect Alzheimer's risk in any one person.
- Identify people who are at high risk for developing Alzheimer's so they can benefit from new interventions and treatments as soon as possible.
- Focus on new prevention and treatment approaches.
Major Alzheimer's Genetics Research Efforts UnderwayAs Alzheimer's disease genetics research has intensified, it has become clear that scientists need many genetic samples to make further progress. The National Institute on Aging supports several major genetics research programs.
To learn more about the Alzheimer's Disease Genetics Study or to volunteer, contact NCRAD toll-free at 1-800-526-2839 or visit www.ncrad.org. |
For More Information
Alzheimer’s Disease Education and Referral (ADEAR) CenterP.O. Box 8250
Silver Spring, MD 20907-8250
1-800-438-4380 (toll-free)
www.nia.nih.gov/alzheimers
The National Institute on Aging's ADEAR Center offers information and publications for families, caregivers, and professionals on diagnosis, treatment, patient care, caregiver needs, long-term care, education and training, and research related to Alzheimer's disease. Staff members answer telephone, email, and written requests and make referrals to local and national resources. The ADEAR website provides free, online publications in English and Spanish; email alerts; a clinical trials database; the Alzheimer's Disease Library database; and more.
Additional information about genetics in health and disease is available from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Visit the NHGRI website at www.genome.gov.
The National Library of Medicine's National Center for Biotechnology Information also provides genetics information at www.ncbi.nlm.nih.gov.
Alzheimer's Association
225 North Michigan Avenue
Floor 17
Chicago, IL 60601-7633
1-800-272-3900 (toll-free)
1-866-403-3073 (TTY/toll-free)
www.alz.org
Alzheimer's Foundation of America
322 Eighth Avenue, 7th floor
New York, NY 10001
1-866-232-8484 (toll-free)
www.alzfdn.org
Glossary
- Allele—A form of a gene. Each person receives two alleles of a gene, one from each biological parent. This combination is one factor among many that influence a variety of processes in the body. On chromosome 19, the apolipoprotein E (APOE) gene has three common forms or alleles: ε2, ε3, and ε4.
- Apolipoprotein E (APOE) gene—A gene on chromosome 19 involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. The APOE ε4 allele is considered a risk-factor gene for Alzheimer's disease and appears to influence the age at which the disease begins.
- Chromosome — A compact structure containing DNA and proteins present in nearly all cells of the body. Chromosomes carry genes, which direct the cell to make proteins and direct a cell's construction, operation, and repair. Normally, each cell has 46 chromosomes in 23 pairs. Each biological parent contributes one of each pair of chromosomes.
- DNA (deoxyribonucleic acid)—The hereditary material in humans and almost all other organisms. Almost all cells in a person's body have the same DNA. Most DNA is located in the cell nucleus.
- Gene—A basic unit of heredity. Genes direct cells to make proteins and guide almost every aspect of cells' construction, operation, and repair.
- Genetic mutation—A permanent change in a gene that can be passed on to children. The rare, early-onset familial form of Alzheimer's disease is associated with mutations in genes on chromosomes 1, 14, or 21.
- Genetic risk factor—A change in a gene that increases a person's risk of developing a disease.
- Genetic variant—A change in a gene that may increase or decrease a person's risk of developing a disease or condition.
- Genome-wide association study (GWAS)—A study approach that involves rapidly scanning complete sets of DNA, or genomes, of many individuals to find genetic variations associated with a particular disease.
- Protein—A substance that determines the physical and chemical characteristics of a cell and therefore of an organism. Proteins are essential to all cell functions and are created using genetic information.
A Service of the National Institute on Aging
National Institutes of Health
U.S. Department of Health and Human Services
Publication Date: June 2011
Page Last Updated: April 9, 2012
Page Last Updated: April 9, 2012
Thursday, 4 April 2013
Why Does apoE4 Make Alzheimer's More Likely? - Dana Foundation
Why Does apoE4 Make Alzheimer's More Likely? - Dana Foundation
By Jim Schnabel July 07, 2011
For the common form of Alzheimer’s that strikes in old age, the greatest risk factor is, of course, old age. But since 1993, Alzheimer’s researchers have puzzled over another major risk factor, a variant of the apoE gene known as apoE4. Compared with people who have other common apoE variants, those with one copy of apoE4 have three times the Alzheimer’s risk and develop symptoms about five years earlier; while those with two apoE4 copies have roughly 12 times the risk, and develop symptoms about a decade earlier.
How does apoE4 exert such a profound risk-worsening, disease-accelerating effect? It now appears that it does so via multiple biological mechanisms, and this complexity has slowed progress in the field. Moreover, the apoE gene codes for apolipoprotein-E, which carries “lipid” (fat) molecules in the brain, and lipid biochemistry is notoriously tricky. “Many people have been discouraged from pursuing investigations in this area, because it’s technically difficult,” says Thomas Wisniewski, a neurologist and apoE researcher at New York University’s Langone Medical Center.
The good news is that after nearly two decades of research on apoE4’s effects in Alzheimer’s, researchers appear to be zeroing in on the ones that matter, and are getting close to clinical trials of drugs that could reverse those effects.
The year after Wisniewski’s paper appeared, researchers in Allen Roses’s laboratory at Duke University reported that apoE proteins bound tightly to the Alzheimer’s-linked protein amyloid-beta (A-beta), and that Alzheimer’s patients, compared with healthy people of the same age, were much more likely to have the apoE4 variant. In their initial sample, about half of patients were apoE4 carriers, while only about 15 percent of age-matched controls were apoE4 carriers. The apoE4-carrying patients also had heavier A-beta deposits than other patients did, not only in their brain matter but also in cerebral blood vessels.
In lab dish experiments, Wisniewski and others soon determined that apoE somehow made A-beta proteins more likely to stick together in long, plaque-making aggregates called fibrils. “The presence of any apolipoprotein-E tended to enhance fibril formation, and the E4 variant was most likely to do that,” says Wisniewski.
But is that really how apoE4 worsens Alzheimer’s?
“ApoE2 and apoE3 [the other two common variants] form big particles and can accept lots of lipids and are very good transporters of lipids throughout the brain, but apoE4 is not as good at this; it forms smaller particles and it is intrinsically more labile [more likely to be degraded],” says Gary Landreth, an apoE and Alzheimer’s researcher at Case Western Reserve University.
ApoE4’s reduced lipid-carrying efficiency appears to leave the brain broadly more vulnerable to the stresses of aging or acute injuries. Following head traumas and strokes, says Wisniewski, “apoE4 carriers tend to do less well.” This reduced lipid-carrying efficiency also helps to explain why apoE4 is moderately associated with atherosclerosis: In the bloodstream, apoE4 does a relatively poor job of grabbing fat molecules and transporting them for proper disposal.
But it turns out that apoE, when covered with lipids, also transports A-beta, because A-beta as it aggregates develops a strong affinity for lipids. For A-beta, this ride often ends within microglial cells, where the protein and its aggregates are digested by strong proteolytic enzymes. ApoE4’s reduced lipid-carrying capacity thus seems to translate into a reduced A-beta removal capacity. Landreth’s lab reported this in Neuron in 2008, and showed that when they used a drug to enhance apoE production in aged “Alzheimer’s mice,” the mice lost most of their A-beta plaques and memory deficits.
Landreth’s and also David Holtzman’s laboratories at Washington University are now separately doing further tests in animal models, to try to confirm and optimize this A-beta clearing effect using different classes of apoE-boosting drugs. “This is now the primary focus of our lab,” says Landreth. “And I would argue that the more apoE you have in the brain, the less amyloid you have, and that’s now consistent with a very substantial literature.”
“Zlokovic’s really good, and there’s no reason to question that work,” says Landreth. “But we still don’t know what fraction of A-beta clearance occurs through its export into the periphery, through this vascular mechanism, and how much is intrinsic due to this proteolytic degradation in the brain.” In other words, more apoE might still be beneficial on balance through its proteolysis-enhancing effect, even if it also reduces A-beta clearance via the bloodstream.
A more radical hypothesis is that apoE4 is actively toxic, so that boosting it in patients would be disastrous. This hypothesis comes from the Gladstone Institute, affiliated to the University of California–San Francisco, where Karl Weisgraber, Robert Mahley and Yadong Huang anchor one of the longest-running apoE research programs.
In 2001, Huang, then a postdoc in Mahley’s lab, reported that apoE proteins could be split by enzymes within neurons to form toxic fragments, and that apoE4 was more likely than other variants to be rendered into such fragments. Transgenic mice that overproduced these fragments developed significant cognitive deficits and even neurofibrillary tangles—amyloid fibrils made of tau protein, which are a marker of severe neuronal stress—like those seen in Alzheimer’s patients.
More recently, Weisgraber’s lab has found evidence, both from lab-dish and mouse studies, that apoE4 can undergo a structural collapse, and in this abnormal “molten globule” form puts stress on the astrocyte cells that make it—effectively shortening their lifespans, and the lifespans of the neurons they service. “Perhaps with age or a second hit such as ischemia [lack of oxygen due to stroke] or a blow to the head, the astrocytes cannot support neurons any longer, and neurons themselves [under stress] start to produce apoE, and that leads to the production of these toxic fragments,” Weisgraber says.
In collaboration with drug-maker Merck, Weisgraber and his colleagues have found compounds that inhibit the apoE-fragment-producing enzyme, as well as compounds that bind to apoE4 and help keep it in a functional structure more like apoE3’s. Merck shelved the project after a recent merger, but Weisgraber says that his group is now trying to get the rights back and restart preclinical development with independent funding. “These are two viable targets that we are going to push forward,” he says.
By Jim Schnabel July 07, 2011
For the common form of Alzheimer’s that strikes in old age, the greatest risk factor is, of course, old age. But since 1993, Alzheimer’s researchers have puzzled over another major risk factor, a variant of the apoE gene known as apoE4. Compared with people who have other common apoE variants, those with one copy of apoE4 have three times the Alzheimer’s risk and develop symptoms about five years earlier; while those with two apoE4 copies have roughly 12 times the risk, and develop symptoms about a decade earlier.
How does apoE4 exert such a profound risk-worsening, disease-accelerating effect? It now appears that it does so via multiple biological mechanisms, and this complexity has slowed progress in the field. Moreover, the apoE gene codes for apolipoprotein-E, which carries “lipid” (fat) molecules in the brain, and lipid biochemistry is notoriously tricky. “Many people have been discouraged from pursuing investigations in this area, because it’s technically difficult,” says Thomas Wisniewski, a neurologist and apoE researcher at New York University’s Langone Medical Center.
The good news is that after nearly two decades of research on apoE4’s effects in Alzheimer’s, researchers appear to be zeroing in on the ones that matter, and are getting close to clinical trials of drugs that could reverse those effects.
ApoE4 enhances amyloid beta clumping
In 1992, Wisniewski reported evidence of apoE proteins in a variety of amyloid protein deposits in the brain and the body. He termed apoE a “pathological chaperone protein” because its frequent presence with aggregated proteins suggested that it somehow triggered or enhanced their aggregation.The year after Wisniewski’s paper appeared, researchers in Allen Roses’s laboratory at Duke University reported that apoE proteins bound tightly to the Alzheimer’s-linked protein amyloid-beta (A-beta), and that Alzheimer’s patients, compared with healthy people of the same age, were much more likely to have the apoE4 variant. In their initial sample, about half of patients were apoE4 carriers, while only about 15 percent of age-matched controls were apoE4 carriers. The apoE4-carrying patients also had heavier A-beta deposits than other patients did, not only in their brain matter but also in cerebral blood vessels.
In lab dish experiments, Wisniewski and others soon determined that apoE somehow made A-beta proteins more likely to stick together in long, plaque-making aggregates called fibrils. “The presence of any apolipoprotein-E tended to enhance fibril formation, and the E4 variant was most likely to do that,” says Wisniewski.
But is that really how apoE4 worsens Alzheimer’s?
ApoE4 impairs microglial clearance of A-beta
As the main transporters of lipids in the brain, apoE proteins perform an important function in bringing these essential building blocks to cell membranes and nerve fibers undergoing development or repair.“ApoE2 and apoE3 [the other two common variants] form big particles and can accept lots of lipids and are very good transporters of lipids throughout the brain, but apoE4 is not as good at this; it forms smaller particles and it is intrinsically more labile [more likely to be degraded],” says Gary Landreth, an apoE and Alzheimer’s researcher at Case Western Reserve University.
ApoE4’s reduced lipid-carrying efficiency appears to leave the brain broadly more vulnerable to the stresses of aging or acute injuries. Following head traumas and strokes, says Wisniewski, “apoE4 carriers tend to do less well.” This reduced lipid-carrying efficiency also helps to explain why apoE4 is moderately associated with atherosclerosis: In the bloodstream, apoE4 does a relatively poor job of grabbing fat molecules and transporting them for proper disposal.
But it turns out that apoE, when covered with lipids, also transports A-beta, because A-beta as it aggregates develops a strong affinity for lipids. For A-beta, this ride often ends within microglial cells, where the protein and its aggregates are digested by strong proteolytic enzymes. ApoE4’s reduced lipid-carrying capacity thus seems to translate into a reduced A-beta removal capacity. Landreth’s lab reported this in Neuron in 2008, and showed that when they used a drug to enhance apoE production in aged “Alzheimer’s mice,” the mice lost most of their A-beta plaques and memory deficits.
Landreth’s and also David Holtzman’s laboratories at Washington University are now separately doing further tests in animal models, to try to confirm and optimize this A-beta clearing effect using different classes of apoE-boosting drugs. “This is now the primary focus of our lab,” says Landreth. “And I would argue that the more apoE you have in the brain, the less amyloid you have, and that’s now consistent with a very substantial literature.”
Will more apoE4 only make things worse?
There are other hypotheses about apoE4’s principal role in Alzheimer’s, and according to these, boosting apoE4 levels in an Alzheimer’s patient would make things worse, not better. Berislav V. Zlokovic’s group at the University of Rochester, for example, reported in 2008 that all apoE variants serve to slow down another important clearance process, in which A-beta is pushed out of the brain into the bloodstream. Zlokovic’s group found that apoE4 slowed down this process more than apoE3 did.“Zlokovic’s really good, and there’s no reason to question that work,” says Landreth. “But we still don’t know what fraction of A-beta clearance occurs through its export into the periphery, through this vascular mechanism, and how much is intrinsic due to this proteolytic degradation in the brain.” In other words, more apoE might still be beneficial on balance through its proteolysis-enhancing effect, even if it also reduces A-beta clearance via the bloodstream.
A more radical hypothesis is that apoE4 is actively toxic, so that boosting it in patients would be disastrous. This hypothesis comes from the Gladstone Institute, affiliated to the University of California–San Francisco, where Karl Weisgraber, Robert Mahley and Yadong Huang anchor one of the longest-running apoE research programs.
In 2001, Huang, then a postdoc in Mahley’s lab, reported that apoE proteins could be split by enzymes within neurons to form toxic fragments, and that apoE4 was more likely than other variants to be rendered into such fragments. Transgenic mice that overproduced these fragments developed significant cognitive deficits and even neurofibrillary tangles—amyloid fibrils made of tau protein, which are a marker of severe neuronal stress—like those seen in Alzheimer’s patients.
More recently, Weisgraber’s lab has found evidence, both from lab-dish and mouse studies, that apoE4 can undergo a structural collapse, and in this abnormal “molten globule” form puts stress on the astrocyte cells that make it—effectively shortening their lifespans, and the lifespans of the neurons they service. “Perhaps with age or a second hit such as ischemia [lack of oxygen due to stroke] or a blow to the head, the astrocytes cannot support neurons any longer, and neurons themselves [under stress] start to produce apoE, and that leads to the production of these toxic fragments,” Weisgraber says.
In collaboration with drug-maker Merck, Weisgraber and his colleagues have found compounds that inhibit the apoE-fragment-producing enzyme, as well as compounds that bind to apoE4 and help keep it in a functional structure more like apoE3’s. Merck shelved the project after a recent merger, but Weisgraber says that his group is now trying to get the rights back and restart preclinical development with independent funding. “These are two viable targets that we are going to push forward,” he says.
Does Estrogen Put the Brakes on Aging in ApoE4-Positive Cells? - AlzForum Alzheimer Research News
Does Estrogen Put the Brakes on Aging in ApoE4-Positive Cells? - AlzForum Alzheimer Research News
 | Does Estrogen Put the Brakes on Aging in ApoE4-Positive Cells? | | |||
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| 15 February 2013. White blood cells age quickly in post-menopausal women who carry the ApoE4 gene, but estrogen slows that decline, scientists report February 13 in PLoS ONE. Natalie Rasgon at Stanford University School of Medicine, California, and colleagues found that telomeres, the protective chromosome ends that are trimmed during DNA replication, shrank faster in aging women who carry at least one copy of this Alzheimer’s disease (AD) risk allele. Because shorter telomeres reflect more rounds of DNA replication, they are seen as an indirect measure of a cell’s age, though shrinking telomeres can also be an indication of oxidative stress or inflammation. Interestingly, women on hormone replacement therapy maintained longer telomeres. “It appears that ApoE4 carriers are at risk for accelerated cellular aging,” Rasgon told Alzforum. Further, she added, “Women receiving hormone therapy may have [ApoE] genotype-dependent responses.” Some studies point to accelerated cell aging in AD. Patients have shorter white blood cell telomeres (see Honig et al., 2006) that dwindle further as the disease progresses (see Panossian et al., 2003). Other studies suggest this is only true in ApoE4 carriers (see Takata et al., 2012). Rasgon previously reported that post-menopausal women who reported more years—and thus more estrogen exposure—between menarche and menopause have longer telomeres (see Lin et al., 2011), as do women on long-term hormone replacement therapy (see Lee et al., 2005). These were cross-sectional studies. No one had determined if the association holds up over time or if ApoE4 status influences it. First author Emily Jacobs, University of California, San Francisco, and colleagues addressed both questions in a randomized, longitudinal trial. The research team measured the length of telomeres in white blood cells of 63 cognitively healthy, post-menopausal women, all of whom had started hormone replacement therapy at menopause and had been taking it for at least one year—one decade on average. Therapy consisted of either conjugated equine estrogen, estradiol, or either of those plus progesterone. Twenty-four participants carried at least one copy of the ApoE4 allele. Researchers randomized half the participants to continue hormone treatment and the other half to suspend it at the start of the trial. Two years later, the scientists measured the chromosome ends again. ApoE4 carriers lost significantly more base pairs than did non-carriers. When estrogen entered the equation, it further divided the women. On average, those who remained on hormone therapy maintained their telomeres regardless of allele status. However, if the women stopped their treatments, ApoE4 carriers lost an average of 322 base pairs per telomere while non-carriers gained 490. The results imply that ApoE4 speeds up cell aging through loss of telomeres, and that estrogen’s impact depends on allele status. The mechanism of action is still unclear, wrote the authors. The findings jibe with “numerous previous studies [that] suggest ApoE4 promotes oxidative stress and inflammation,” Mark Mattson, National Institute on Aging, Baltimore, Maryland, told Alzforum in an e-mail. Further studies will be needed to determine if the apolipoprotein exerts a direct influence on telomeres, and whether shorter telomeres in immune cells might mediate ApoE4’s effects on the aging brain and other organs, he wrote. Results also indicate that if women with ApoE4 begin estrogen therapy as soon as menopause starts, they may be able to protect themselves against cell decline. “I find that fascinating,” said Phyllis Wise, University of Illinois at Urbana-Champaign. “We are learning that estrogen’s effects are pleiotropic, and this paper suggests they are even broader than we had appreciated before—they can get into the arena of chromosomal structure.” Estrogen’s precise influence on telomeres is unclear, wrote the authors, but previous studies reported that the hormone stimulates expression of part of the telomerase complex and raises the activity of telomerase, the enzyme that adds DNA to telomere ends (see Misiti et al., 2000, and Calado et al., 2009). Estrogen also has antioxidant properties (see Wong et al., 2008), which could indirectly stabilize telomeres. Treatment does not seem to help non-carriers maintain their telomeres. In fact, stopping the treatment actually led to their growth, a phenomenon still under investigation by scientists, wrote the authors. Why might estrogen affect ApoE4 carriers and non-carriers differently? Rasgon and colleagues are unsure, but write that it could relate to ApoE gene expression. A previous study reported that estradiol boosts ApoE translation (see Srivastava et al., 1997). Regardless of the mechanism, these findings may help experts make sense of contradictory evidence about the benefits and dangers of hormone replacement therapy. For example, some studies suggested that it decreases risk for dementia (see ARF related news story), while others indicated the opposite (see ARF related news story). ApoE status seems to define subsets of women who respond differently to estrogen, said Rasgon. “This study moves us a step closer to understanding which groups of women may benefit from hormone therapy versus those who will not.” Because of the small sample size, this study was unable to tease apart whether different types of estrogen replacement have different effects. Rasgon said she plans to address that issue in future work, in addition to testing whether her findings hold up in a larger sample. As of now, results are too preliminary to make clinical recommendations about genetic testing for ApoE4, or about which subgroups should take supplemental estrogen, Rasgon told Alzforum.—Gwyneth Dickey Zakaib. Reference: Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL. Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use. PLoS One. 2013;8(2):e54713. Abstract |
New clues on how ApoE4 affects Alzheimer's risk, May 16, 2012 News Release - National Institutes of Health (NIH)
NIH-funded research provides new clues on how ApoE4 affects Alzheimer's risk, May 16, 2012 News Release - National Institutes of Health (NIH)
Embargoed for Release
Wednesday, May 16, 2012
1 p.m. EDT
The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain's blood vessels. Normally, this barrier allows nutrients into the brain and keeps harmful substances out.
The study appears today in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.
“Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," Dr. Zlokovic said. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system," he said, referring to the system of blood vessels that supply the brain.
The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties. ApoE2 is thought to play a protective role against both Alzheimer's and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions. Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however,inside the brain, exactly how ApoE4 contributes to Alzheimer's disease has been a mystery.
Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE. The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice's brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.
"The study demonstrates that damage to the brain's vascular system may play a key role in Alzheimer's disease, and highlights growing recognition of potential links between stroke and Alzheimer's-type dementia," said Roderick Corriveau, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. "It also suggests that we might be able to decrease the risk of Alzheimer's disease among ApoE4 carriers by improving their vascular health."
The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4. The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain. An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.
"These findings point to cyclophilin A as a potential new drug target for Alzheimer's disease," said Suzana Petanceska, Ph.D., a program director at NIH's National Institute on Aging (NIA), which also funded Dr. Zlokovic's study. "Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer's in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer's."
Alzheimer's disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain. Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer's that appears early in life, between age 30 and 60.
However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer's disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer's disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.
Dr. Zlokovic's study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain. On the other hand, Dr. Zlokovic's data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain. Some therapies under investigation for Alzheimer's focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.
This research was funded by grant NS034467 from NINDS, and grants AG023084, AG039452 and AG013956 from NIA.
NINDS (http://www.ninds.nih.gov) is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.
NIA (http://www.nia.nih.gov) leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center at http://www.nia.nih.gov/Alzheimers.
Embargoed for Release
Wednesday, May 16, 2012
1 p.m. EDT
NIH-funded research provides new clues on how ApoE4 affects Alzheimer's risk
Common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer's disease, but the gene's role in the disease has been unclear. Now, researchers funded by the National Institutes of Health have found that in mice, having the most risky variant of ApoE damages the blood vessels that feed the brain.The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain's blood vessels. Normally, this barrier allows nutrients into the brain and keeps harmful substances out.
The study appears today in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.
“Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," Dr. Zlokovic said. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system," he said, referring to the system of blood vessels that supply the brain.
The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties. ApoE2 is thought to play a protective role against both Alzheimer's and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions. Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however,inside the brain, exactly how ApoE4 contributes to Alzheimer's disease has been a mystery.
Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE. The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice's brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.
"The study demonstrates that damage to the brain's vascular system may play a key role in Alzheimer's disease, and highlights growing recognition of potential links between stroke and Alzheimer's-type dementia," said Roderick Corriveau, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. "It also suggests that we might be able to decrease the risk of Alzheimer's disease among ApoE4 carriers by improving their vascular health."
The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4. The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain. An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.
Destructive enzymes (shown in green) become more active and weaken the blood-brain barrier in mice that are genetically engineered to produce only human ApoE4 (right), rather than mouse ApoE (left). Image courtesy of Robert Bell, Ph.D., University of Rochester Medical Center, New York.
Alzheimer's disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain. Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer's that appears early in life, between age 30 and 60.
However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer's disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer's disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.
Dr. Zlokovic's study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain. On the other hand, Dr. Zlokovic's data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain. Some therapies under investigation for Alzheimer's focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.
This research was funded by grant NS034467 from NINDS, and grants AG023084, AG039452 and AG013956 from NIA.
NINDS (http://www.ninds.nih.gov) is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease — a burden borne by every age group, by every segment of society, by people all over the world.
NIA (http://www.nia.nih.gov) leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center at http://www.nia.nih.gov/Alzheimers.
Wednesday, 27 March 2013
Animal Pharm: Ancient Transporters: HDL and LDL Lipoproteins Carry Precious Cargo
Animal Pharm: Ancient Transporters: HDL and LDL Lipoproteins Carry Precious Cargo
Sunday, March 24, 2013
The NCEP/ATP III Cholesterol Guidelines Bogus: 'Cholesterol Limits Lose Their Lustre'
Conventional medicine at this time uses Big Pharma-funded assessment and treatment guidelines which promote the use of statins as first line in order to 'treat' the LDL (goal less than 70, 100, or 130 mg/dl) to targets based on risk stratification, e.g. age, prior family history coronary events, low HDL, smoking and presence of hypertension.
What are the true root causes of these 'risk factors' in light of evolution (if you believe in evo)? Is LDL really 'bad'?
Indeed.
Hormonal havoc and energy balance dysregulation caused by neolithic excess of refined n-6 vegetable oils, high fructose GMO-corn syrup, intestinal permeability, refined carbohydrates, sugar, mercury/arsenic/lead/cadmium, gut dysbiosis, failures of vitamin/mineral absorption by the action of phytates and lectins, and endocrine-disrupting consequences of pesticides and other environmental persistent-organic toxins are more likely factors.
And they have nothing to do with LDL. Half of heart attacks occur in individuals where the LDL is already less than 70 mg/dl.
The old cholesterol guidelines NCEP/ATP-III that were first put out over a decade ago are now being revamped. Nature has a new article on the future NCEP/ATP-IV.
'Since 2002, when ATP III called on doctors to push LDL levels below set targets, the concept of low cholesterol has become synonymous with heart health. Patients brag about their cholesterol scores, physicians joke about adding statins to drinking water, and some hospitals reward doctors when patients hit cholesterol targets.'
~~~~~~~~~~~~~~~~~
LDL Affected by Apo E Alleles
Amount of LDL-C and LDL-P Determined by ApoE
We each individually and uniquely have widely varied lipoprotein patterns (LDL, TG, HDL) determined by our genetics, the microniche our ancestors evolved and survived in, and our apolipoprotein E. Apo E is mainly found in HDL and LDL particles but also free form in the circulation as well. It aids lipoprotein particles in docking up to cell membranes to unload contents into a destination cell or the liver.
Apo E determines the LDL-quantity. Three alleles for apoE exist and we each have 2 copies from a mix from our parents - E2, E3 or E4. ApoE to me is like a special key to unlock troubled doors. Those with E4 alleles have lipoproteins with the least apoE (perhaps true H-G, more cholesterol hung out longer in circulation). Geographically the incidence of E4 rises toward a northern distribution in Europe, away from the equator. Those with E2, more apoE (perhaps more agarian adapted). Energy flux patterns and metabolism are mildly different: E4, more carbohydrate sensitive; E2, less.
Many 'cardiac' rat models use apoE-deficient mice because these animals inevitably develop horrific plaque and atherosclerotic disease and blocked arteries, on high carb rat chow.
The lower the apo E alleles, the lower the total cholesterol [ref 2]. The researchers (above) demonstrate the LDL and HDL trend in parallel with total cholesterol and the higher the E. Conversely, triglycerides grow higher, the lower the apo E.
It seems finally that the medical community be viewing the true science and questioning the BS. If LDL is genetically determined by the apoE type and is a false coronary risk factor, then what is the true cause of coronary events, MIs, angina and plaque destabilization?
Naturally if one is apoE 4/4 (rare), then one is likely to have the highest LDL amongst friends and aquaintances. Is it harmful? Depends. ApoE 4/4 are more likely to be HIGHLY insulin resistant, inflamed and carbohydrate sensitive. In the modern industrial environment where whole food, ancestrally-inclined meals are endangered species... perhaps.
Are apoE 4/4 the true survivors of Earth? They are less likely to suffer from infections or starvation which were the major reasons for mortality outside of predation prior to neolithic times. Add to that vascular protection from Lp(a) from vitamin C-deficiency hemolysis and one has a winning combination for longevity given the right circumstances when inflammation is well regulated and gene-protein expression optimal.
The higher the LDL, the higher the Lp(a), the better survival?
Size of LDL Determined by Diet and Lifestyles: Microecological Niche
Environment dictates the LDL-particle-size. Exercise, high saturated fat, cholesterol-intake, low carb, low fructose, low omega-6/omega-3 ratio and antioxidants/flavonoids are factors that high influence and create more large, buoyant, resistant-to-oxidation LDL-particle-sizes, despite apoE status.
LDL Less Than 70 mg/dL is Dangerous
So why are cardiac 'experts' prescribing a one-size-fits-all LDL goal of less than 70 mg/dl and statins for all individuals with heart disease, diabetes, aneurysms, chronic kidney disease, and other atherosclerotic equivalents?
Does this take into account apoE status and genetically-predetermined LDL amounts?
An LDL less than 70 mg/dl is not magic. At TYP, very rarely did I observe CAC Agatson coronary artery calcification reversal. Members were on potent statins or suppressed their LDL to (unnatural) goals of 60 mg/dl.
Seth Roberts did achieve reversal, by consuming cholesterol (butter). No pharmaceuticals.
I have noticed countless, sad times where statins do nothing to regress or stop the progression plaque. In fact, they are associated with progression in 12 out 14 published coronary calcification studies.
Many studies show that statins are also highly associated with cancer, increased incidence of congestive heart failure (CHF), accidents, violent death, depression/suicide, and all-cause mortality.
Low cholesterol and low LDL, independently, additionally are significantly correlated to cancer, increased incidence of chronic heart failure and all-cause mortality.
Let's probe this... because statins lost their allure years ago for me.
Overview of TransportersEvery vital vitamin, hormone and steroid exists both 'free' and available in the blood circulatory system and bound to degrees to a transporter-protein. Some vitamins, hormones and steroids interact directly with receptors on cell membranes and other cases the transporter-protein interacts with receptors on cell membranes to translocate the vitamin, hormone or steroid into the cell. From the gut to the liver, food gets processed into free fatty acids, triglycerides (3 fatty acids attached to one sugar backbone) and bundled into particles with antioxidants for circulation and storage in peripheral tissues like the muscles, adipose, gonads, and adrenals.
Cholesterol
Every cell membrane is composed of cholesterol -- this is the asphalt and infracture of our communication highways. Another way to appreciate these conductors of electronic charge is to recognize that cholesterol in our cellular membranes is analogous to the DSL or Comcast cables of our high-speed computers, our brain and nervous systems.
How do 'dropped signals' feel? Perhaps your cholesterol is impaired?
Roles of cholesterol:
a) formation of cellular walls
b) formation of aldosterone (important for blood pressure regulation)
c) formation of the sex hormones
d) formation of Vitamin D
e) formation of bile to eliminate and recycle wasted and precious fat-soluble molecules
f) formation of corticosteroids which are involved with glucose regulation and suppressing inflammation
g) formation of steroidal derivatives including the vital and potent antioxidant Ubiquinol/ CoenzymeQ10
h) antioxidant with scavenger functions for harmful microbial endotoxins
Without cholesterol, humans cannot survive, brain and organ function deteriorate, and eventually cancer and other inflammatory conditions are triggered. Without sufficient cholesterol, cortisol, testosterone, progesterone, estrogens and other potent steroidal hormones cannot be made.
Statins Lower Testosterone
As one would expect, statin pharmaceuticals which block the rate-limiting enzyme for cholesterol production in the liver and all extrahepatic sites (e.g. BRAIN, ADRENALS, TESTICLES, etc), HMG-CoA reductase, are highly associated in reduction of total testosterone and subsequent low testosterone signs and symptoms [ref 3-9].
Low testosterone is also considered a risk factor for heart disease due to the inflammatory state that occurs including obesity, metabolic syndrome, hyperinsulinemia, poor immunity and diabetes[ref 7]. I question the prudence in the strategy behind initiating a statin and potentially lowering testosterone further, thereby inducing yet another cardiac risk factor. Would you like to be a eunuch?
Diabetic eunuch? Chuckle with Peter at Hyperlipid:
Sta'ins, CoQ, diabetes and Dr Andreas Eenfeldt's link
Ancient Transporters
Our lymphatics and blood vessels form the highways that transport nutrition, oxygen and necessary constituents for organ maintenance and rebuilding. They also remove wastes, CO2 and recycled cellular parts and spent steroid hormones for elimination via the gut or 'recycling' via enterohepatic recirculation.
How are antioxidants, pro-vitamins, vitamins, pro-hormones and hormones from our food and endocrine glands/tissues carried to the peripheral sites? Ancient tranports have evolved (if you believe in evolution) in all living systems for the role of carrying these items to the appropriate target tissues.
Vitamin A (retinol): free and bound to RBP (retinol-binding protein)
Vitamin D (cholecalciferol): free and bound to VDBP (vitamin D binding protein, aka Gc globulin)
Estrogen (E1 E2 E3): free and bound to SHBG (sex-hormone binding globulin) and EBP (estrogen-binding protein)
Testosterone, DHT: free and bound to SHBG and ABP (androgen-binding protein)
Progesterone: free and bound to SHBG and PBP (progesterone-binding protein)
DHEA: free and bound in HDL particles
Cortisol: free and bound to CBP (cortisol binding protein)
Ubiquinol/CoQ10: bound in HDL and LDL
Menaquinones (MK4 to 9; vitamin K2): bound in HDL and LDL
Retinoids (vitamin A): bound in HDL and LDL
Carotenoids (vitamin A): bound in HDL and LDL
Tocopherols, tocotrienols (vitamin E): bound in HDL and LDL
Minerals - iodine zinc selenium copper: Free form and bound in HDL and LDL
Cholesterol: Free form and bound as Esters in HDL and LDL
See prior animal pharm: LDL, HDL Transporters
Purpose of LDL and HDL Transporters: Evo Perspective
Lipid transport and delivery systems existed in the earliest animals including insects. Our lipoprotein systems are not that dissimilar [ref 1]. Fat-soluble nutrients like cholesterol, carotenoids, vitamin E and coenzyme Q10 would form a two-layered oil-vinegar like concoction in our blood circulatory system if it were not for specialized transporters for fat-like substances.
HDLs are much more compact and smaller in size than LDL. They fit between the gap and communication junctions in the endothelium (lining of blood vessels). Whereas, LDL particles are larger and barely fit between normal gap junctions of endothelium. If the LDL particles however are 'small' their purpose is different. They are more oxidizable and denser. This tighter conformation allows movement into damaged endothelium and traumatized and inflammed tissues to provide ammunitions for macrophages to do their work and relinquish the waste and end products for disposal. I don't read French (see below if you do).
Once HDL and LDL are done, they can re-enter the blood stream, return to the liver for future processing.
Ubiquinol Protects Against Failure of the Heart and All OrgansUbiquinol is lowered by statins since ubiquinol and its derivatives are cholesterol structures [ref 19]. Unfortunately ubiquinol is necessary in all cells and mitochondria where it serves a role as mandatory antioxidant and a recycling nazi [16-18]. Low ubiquinol in the blood is associated with faster progression of heart failure [ref 17].
Statins lower the LDL contents of ubiquinol and all fat-soluble nutrients, vitamin E and carotenoids. Does this have consequences?
Prior animal pharm: Role of Ubiquinol
Higher the Cholesterol, Higher the CHF Survivorship
Our understanding of survival and the evolution of insulin resistance provides the foundation to understand the causes of all diseases of modern civilizations including CHF. The studies bear this out in which the higher glucose and higher insulin resistance, the higher the association to mortality in CHF [ref 12-16]. Interestingly several studies demonstrate the lower the cholesterol, the higher the CHF mortality. Some clinicians raised the potential risks of statins in light of these adverse outcomes in individuals with CHF [ref 31].
In patients with progressive CHF, their LDL are all small packages which can barely hold vital antioxidants like ubiquinol. Add a statin which deplete the crucial functioning ubiquinol for pumping heart muscles, spelling catastrophe.
Low Cholesterol Associated With Increased Cancer Incidence: 17-Year Basel Study
The prospective 17-year Basel study showed a 2-7 fold increase in cancer mortality in males at various cancer sites with low serum cholesterol. This study confirms what some of the other cancer epidemiology studies have already shown. Researchers tested blood from 2974 participants stored from 1971-1973. Co-founders such as vitamin blood levels were adjusted for in the analysis.
Quality will always trump quantity of LDL.
Prior animal pharm: Cardio Controversies -- Tale of 2 LDLs
Carcinogenicity of Statins: The Lower the Final LDL, the Higher Cancer Rate
Finally the statin and lipid-lowering drug trials themselves have demonstrated that the lower the cholesterol, the higher mortality from cancer in a meta-analysis in JACC, 2007 by Alsheikh-Ali et al [ref 27]. Plotting final LDL with cancer, the graph depicts a firm association between the lower the LDL and increased cancer incidences.
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6 comments:
- Calvin said...
- ♦
- Chip Spitter said...
- Good post, thanks for your continued work in this area. Being an E4/E4, I always like to read more about it, even if there's chance it is just confirmation bias. Have a good one.
- Anonymous said...
- I think you mis-cited the last paragraph? Ref[27] is a meta-analysis of rodent studies, but the figure you posted is from: "Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer", which you didn't cite.
- George Henderson said...
- Great post and good to hear from you again. Everyone needs to know this stuff. Seems to me some interventions - fish for example - might lower LDL (maybe, I'm not certain it does) - in ways that don't compromise health (activation of PPAR-alpha meaning slightly more fat burned in liver instead of exported). Others might elevate LDL (eating a big chocolate cheesecake everynight) but compromise health due to glucose-insulin loads and empty calories. So it's not the rise or fall in LDL per se, but whatever caused it. And as very different things and different processes can cause similar-looking changes in LDL and HDL we should ask are those THINGS desirable in our lives - and bugger the cholesterol numbers they result in. A cholesterol number should never cause you to consume a harmful thing or avoid a nutritious one. IMO.
- Dr. B G said...
- Anon -- Thnx! Fixed. Both statins and controls actually have increased incidence of cancer at the lower LDLs. In rodents any dose of statin is carcinogenic. Humans are different but I'm not sure how. George, I appreciate the posts on your blog as well. FASCINATING STUFF ;) Yes I try not rely on labs but sometimes one has to (love/hate). Being in China, obtaining labwork is challenging to say the least. For instance many on statins have no idea they are doing harm to each and every mitochondria (particularly liver ones, no?). Muscle punch biopsy studies have demonstrated damage to muscles due to statins despite totally 'normal' CPK. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581-5. England JD, Walsh JC, Stewart P, Boyd I, Rohan A, Halmagyi GM. Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors - simvastatin and pravastatin. Aust N Z J Med 1995;25:374-5. Labs are just a surrogate for what a person is trying to discern objectively. http://drbganimalpharm.blogspot.jp/search/label/SHOW%20ME UR RIGHT ON. So many limitations! I enjoyed your example of trends with fish v. cheesecake. Depending on the person (E2 v. E4) LDL may go up or down!
- Dr. B G said...
- Objective ways to assess function and health of mitochondria (and statin damage) is to measure mitochondrial CoQ10, TCA and Kreb cycle intermediaries and organic acids. http://www.metametrix.com/learning-center/articles/2006/why-test-for-coenzyme-q10
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