Simvastatin and the ApoE4 Allele

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Fiver
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Re: Simvastatin and the ApoE4 Allele

Post by Fiver »

Hi Harrison - it does seem harder than it should be to see clear, consistent results in big studies, doesn't it? I spent some time recently re-reading those statin studies. It does seem that those big studies recalling past statin usage through middle age show positive effects while those assigning patients to groups and following them forward (for much shorter periods of time, usually at later ages) have not shown benefits. So I agree, it seems to be beneficial when used through middle age, which I guess makes sense.

I actually couldn't find much actual evidence that the different statins penetrate the BBB differently. If someone has those studies I would love to hear about them - it makes logical sense, just haven't seen the data. In the few big, long term retrospective studies considering more than one statin they all seem to perform similarly. The samples sizes are different for each statin in these studies, because some were/are more popular than others, so the statistical power is unequal....but they really look similar. It I look really hard maybe I start to think that I see the hydrophillics like atrovastatin working just a tiny bit better....but I'm probably reading too much into the data.

The more I read the less clear it seems....
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KatieS
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Re: Simvastatin and the ApoE4 Allele

Post by KatieS »

Fiver wrote:Hi Harrison - it does seem harder than it should be to see clear, consistent results in big studies, doesn't it? I spent some time recently re-reading those statin studies. It does seem that those big studies recalling past statin usage through middle age show positive effects while those assigning patients to groups and following them forward (for much shorter periods of time, usually at later ages) have not shown benefits. So I agree, it seems to be beneficial when used through middle age, which I guess makes sense.

I actually couldn't find much actual evidence that the different statins penetrate the BBB differently. If someone has those studies I would love to hear about them - it makes logical sense, just haven't seen the data. In the few big, long term retrospective studies considering more than one statin they all seem to perform similarly. The samples sizes are different for each statin in these studies, because some were/are more popular than others, so the statistical power is unequal....but they really look similar. It I look really hard maybe I start to think that I see the hydrophillics like atrovastatin working just a tiny bit better....but I'm probably reading too much into the data.

The more I read the less clear it seems....
Did you mean rousuvastatin, a potent yet hydrophilic statin? Atrovastatin is also potent, yet lipophilic. Still I agree that the statins tend to perform similarly and actual AD prevention is unclear. Should you have a non-demented parent or sib who also has Apoe4 and has been on a statin for decades, this tilts the scale towards whatever statin they use. I suspect there is a genetic subset that does benefit.
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Re: Simvastatin and the ApoE4 Allele

Post by popo »

I am new to this forum. I just learned from my raw data upload from 23andMe to Prothease that I am A3/A4 markers. In addition I have rs4363657(C;C) with a 17x increased myopathy risk for statin users.

Hence my conundrum is how to start a safe statin regimen to reduce my elevated LDL at 149. Total Cholesterol at 220, HDL at 54 and T. Chol/HDL Ratio at 4.1. Im 62 years old, 5'7" and 150 pound athletic male.

I have read discussion in this forum that low dosage of various statins at 20mg. might be beneficial in lowering cholesterol without risk of myopathy. However this low dosage is unlikely to be a long term therapeutic benefit for reducing the risk of Alzheimer's disease.

It appears that I have a Catch 22. I have risk of 2x to 3x Alzheimers. I have 17x increased risk of myopathy from statin usage. If I don't use statins my LDL will not drop and my long term risk of Alzheimers is not addressed with a statin regimen.

What type of physician would be the most qualified to review my blood results, risk facts from bio markers, and prescribe and manage a statin regimen?
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Re: Simvastatin and the ApoE4 Allele

Post by Verax »

popo wrote: It appears that I have a Catch 22. I have risk of 2x to 3x Alzheimers. I have 17x increased risk of myopathy from statin usage. If I don't use statins my LDL will not drop and my long term risk of Alzheimers is not addressed with a statin regimen.
popo, I'm not a physician, and I have similar problems I might discuss with a cardiologist, but I did see this article, https://www.ncbi.nlm.nih.gov/pubmed/237 ... t=Abstract Am Heart J. 2013 Jun;165(6):1008-14. doi: 10.1016/j.ahj.2013.01.025. Epub 2013 Apr 10.
"Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy."

One of the major problems of direct-to-consumer DNA testing without 23andme's following genetic counseling guidelines is that we naturally tend to focus on single outstanding risk factors instead of the polygenic blend expression that relates to causality and not correlation. All this is new personalized precision mediciine, and convincing evidence slim, but maybe you should discuss trying rosuvastatin 20mg?
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Re: Simvastatin and the ApoE4 Allele

Post by Verax »

popo wrote: this low dosage [20mg statin] is unlikely to be a long term therapeutic benefit for reducing the risk of Alzheimer's disease.
Last year the JAMA Neurology review concluded, "Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively)."
https://jamanetwork.com/journals/jamane ... le/2591317 A very good explanation of that risk, amounting to less than 1% absolute, is at https://www.healthnewsreview.org/2016/1 ... lines-say/

These studies have so far not identified and followed carriers of ApoE4, and even though they are large observational studies have lacked diversity of population and have many methological difficulties, as the Cochrane Collaborative has pointed out. The authors suggested larger trials of such cheap drugs to prevent expensive AD, but it seems nobody wants to pay for it, as benefits appear moderate, certainly for those who start off-patent drugs in old age rather than in midlife. https://www.alzforum.org/news/research- ... imers-risk https://www.statnews.com/2017/02/09/alz ... e-statins/

There doesn't seem yet to be any clear idea which statin to prescribe, so if there is lower myalgia risk for rosuvastatin for your phenotype then I will consider it (talk to your cardiologist). http://n.neurology.org/content/early/20 ... 0000004818 "Comparative effect of statins on the risk of incident Alzheimer disease" (Dec 15, 2017) The author commented to Medscape: "Our results suggest that there isn't a clear difference between individual types of statins. And in terms of clinical decision making when choosing a statin, the effect on the risk of Alzheimer's should not be a consideration." https://www.medscape.com/viewarticle/890484
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Re: Simvastatin and the ApoE4 Allele

Post by Ski »

I would say that the majority of statin users on this forum, including myself, take it because they have documented vascular disease. Id say that is your first step in making any informed decision on whether to go a pharmaceutical route. I personally would never take it for what appears to be very conflicting evidence for Alz prevention. The well documented negative metabolic effects statins can inflict are real and not worth it IMO.

Also, as a rosuvastatin user, 20 mg in the drug is pretty hefty and not what I would consider low dose by any means. Do a drug comparison to see the different lipid lowering effects. 10mg of Rosuvastatin is similar to the maximum dosage of some others. Also there is alternating day therapy that I have not done with a statin but is also indicated in those with myopathies. I can tell you that I can almost get the exact same lipid lowering effect on taking Zetia 3x per week as I can taking it every day. Just an example.
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Re: Simvastatin and the ApoE4 Allele

Post by Harrison »

Fiver wrote:I actually couldn't find much actual evidence that the different statins penetrate the BBB differently. If someone has those studies I would love to hear about them - it makes logical sense, just haven't seen the data...
...The more I read the less clear it seems....
Ain't that the truth. To muddy the waters, here is a study that suggests fungus-derived statins increase the risk of AD: https://www.ncbi.nlm.nih.gov/pubmed/29247073

Here is older data from cell culture suggesting differences in BBB penetration: https://www.ncbi.nlm.nih.gov/pubmed/21098985

Here is a review that attempts to objectively cover the question: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830056/

It's quite possible that there are no AD preventative effects of statins, or no differences between lipophilic and hydrophilic statins. It's also possible there are small differences that would require years of treatment and lots of subjects to see, particularly if there are apoE genotype-specific effects.

Edit: Just saw Ski's response, and I agree heartily. I have had borderline-high cholesterol but my physician does not think it is worth it for me to take a statin at the present time.
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Re: Simvastatin and the ApoE4 Allele

Post by floramaria »

popo wrote:I am new to this forum. I just learned from my raw data upload from 23andMe to Prothease that I am A3/A4 markers. In addition I have rs4363657(C;C) with a 17x increased myopathy risk for statin users.

Hence my conundrum is how to start a safe statin regimen to reduce my elevated LDL at 149. Total Cholesterol at 220, HDL at 54 and T. Chol/HDL Ratio at 4.1. Im 62 years old, 5'7" and 150 pound athletic male.

I have read discussion in this forum that low dosage of various statins at 20mg. might be beneficial in lowering cholesterol without risk of myopathy. However this low dosage is unlikely to be a long term therapeutic benefit for reducing the risk of Alzheimer's disease.

It appears that I have a Catch 22. I have risk of 2x to 3x Alzheimers. I have 17x increased risk of myopathy from statin usage. If I don't use statins my LDL will not drop and my long term risk of Alzheimers is not addressed with a statin regimen.

What type of physician would be the most qualified to review my blood results, risk facts from bio markers, and prescribe and manage a statin regimen?
Welcome to the site, Popo. You raise many important questions such as what physician to consult and how to balance risk factors; that is a dance many of us are doing. In my own case I find that I am doing more research on personal risk factors than my PCP ever offers, which is the situation many of us find ourselves in; we are educating ourselves, and sometimes our PCPs, and making the best choices we can. You will find there is a lot of information on this website on the subject of statins, and discussion of individual experiences that may help guide you. You can use the search function (magnifying glass) to find threads that have strong personal relevance.

A great starting place for reducing your overall AD risk is the Primer, an excellent, common sense overview of proven risk reduction strategies, including many important and beneficial lifestyle changes you can implement on your own.

We are happy you are joining us here. You will find a tremendously supportive community as well as accumulated knowledge both from personal experience and from shared resources. Please continue to post your questions.

and again, a warm welcome!
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popo
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Re: Simvastatin and the ApoE4 Allele

Post by popo »

Does anyone have an excellent doctor who is up to date on statin usage as a preventative treatment for risk of AD onset as a result of being A3/A4? I live in the San Fransisco Bay Area. Thank you,
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Re: Simvastatin and the ApoE4 Allele

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popo wrote:Does anyone have an excellent doctor who is up to date on statin usage as a preventative treatment for risk of AD onset as a result of being A3/A4? I live in the San Fransisco Bay Area. Thank you,
Hi popo,
I have two friends who have recently needed to find new cardiologists. In one case, she went to a local teaching hospital and asked about someone with specific experience in the condition a cardiologist in another state had diagnosed as serious in her husband. The new cardiologist identified several issues, including one that needed to be treated first, and a year later, her husband is in better health, has lost weight and exercises more--and had two successful surgeries from a referred surgeon.
In the other, a friend asked her health plan provider for the name of a relatively new cardiologist who was recognized as being up on research after her long-time cardiologist was unaware of ApoE 4/4 and was not bothered by new testing showing vascular disease. At the first visit, he brought up her 4/4 status (It's in her records) and then listed the various issues associated with cardiology that might be relevant to her care. She obviously was won over immediately. You may want to try a similar approach: talk with either your insurance provider about cardiologists in the area, or call UCSF.

Just as an example to show what is available, it's possible to see staff biographies of the cardiologists on the UCSF website. Here are 3 that seem interested in the genetics of preventive cardiology. None of these are known to me; you'll probably want to do some research and talk with your primary care doctor. If you find someone who is ApoE 4-aware, feel free to post a recommendation on our Practitioner Review Forum. Practitioner Reviews
Rima Arnaout, MD Cardiologist
Rima Arnaout is a cardiologist who enjoys partnering with her patients to determine the best course of treatment to help them make informed medical decisions. She is also interested in cardiovascular genetics and multimodality imaging. An assistant cardiology professor at UCSF, Arnaout studies the genetic basis of heart development and disease at the Cardiovascular Research Institute, with a special interest in cardiomyopathy and arrhythmia.
Arnaout earned her medical degree at Harvard University and completed a residency in internal medicine at Massachusetts General Hospital and completed a cardiology fellowship at UCSF. She has been working on a National Institutes of Health-funded research project on the genetics and structure of trabecular myocardium (irregular heart muscles) in heart disease for two years. She is a member of the American Heart Association, American College of Cardiology, American Society of Echocardiography, American Society of Nuclear Cardiology and Sarnoff Cardiovascular Research Foundation.

Rahul Deo, MD, PhD Cardiologist Dr. Rahul Deo is a cardiologist in the Cardiovascular Care and Prevention Center at UCSF Medical Center who is particularly interested in patients and their families with inherited cardiovascular disease, particularly cardiomyopathies or diseases of the heart muscle. Deo, a native of Canada, earned a medical degree at Cornell University Medical College and a doctorate in molecular biophysics at Rockefeller University, both in New York, as part of the Tri-Institutional M.D.-Ph.D. Program. He completed an internship and residency in internal medicine at Brigham and Women's Hospital and a cardiology fellowship at the Massachusetts General Hospital in Boston. He then conducted postdoctoral research in human genetics and computational biology at Harvard Medical School. Deo's research interests focus on large-scale genetic and genomic data to develop personalized diagnosis and therapy in cardiovascular medicine. He is an associate professor in residence in medicine at UCSF.

Ethan Weiss, MD Cardiologist Dr. Ethan Weiss is a cardiologist specializing in general cardiology. His special interests include preventive cardiology, genetics of coronary disease, risk assessment and heart disease in the young. In his research, Weiss uses genetic models to better understand the mechanism of metabolic disorders such as obesity, fatty liver disease, and diabetes. He also studies the blood clotting system and has interest in identifying novel ways to safely block clots associated with diseases such as heart attack and stroke without causing an increase in bleeding.
Weiss earned a medical degree at Johns Hopkins University School of Medicine. He completed an internship and residency on the Osler Medical Service of the Johns Hopkins Hospital. He came to the University of California, San Francisco in 1998 as a cardiology fellow and is currently an associate professor of medicine.
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