"Major News": Plasma APOE levels, not genotype, related to Alzheimer/s

[Stavia]

Rep I can see it on the library database but it keeps timing out. I'll try again tomorrow.

[RichardS]

More head spinning:

ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Full text: http://journals.plos.org/plosmedicine/a ... ed.0030176

Editors' Summary
Background.

Atherosclerosis is a common disorder of the blood vessels. Blood lipids (fatty substances, for example cholesterol and other substances collect on the inner walls of the vessels and form layers, known as plaques. Eventually, these plaques can interfere with blood flow though the blood vessels. They can also break apart, causing debris to travel through the bloodstream to other parts of the body and block vessels there. This rupture is a common cause of heart attack and stroke. Scientists believe that inflammation (that is, activation of the body's immune system) helps cause atherosclerosis. ApoE is a protein present in the blood that influences how cholesterol and other fats are made and removed from the body. ApoE can also have an effect on inflammation. Different people have different levels of apoE in their blood, depending on which version of the APOE gene (which codes for the apoE protein) they have as well as other factors.
Why Was This Study Done?

Knowing that apoE can influence both blood lipid levels and inflammation, and that the specific version of the APOE gene can affect a person's risk for cardiovascular disease, this study was designed to test whether blood levels of apoE can then affect the risk of death from cardiovascular disease (such as heart attack and stroke).
What Did the Researchers Do and Find?

They studied 546 patients who were 85 years and older. All patients gave blood samples within a month after their 85th birthday and then every following year within a month of their birthday. Within the five years of the study, 274 participants died, 115 of them from cardiovascular disease. The researchers analyzed the blood samples in the following ways. They measured apoE protein levels in the first blood sample and also determined the variants of the APOE gene for each participant. For the first and all following yearly blood samples, they also measured cholesterol, other lipids, and a substance called CRP. CRP is a marker of inflammation and known to be raised in patients with cardiovascular disease. The researchers found that in these patients, those who had high levels of apoE at age 85 had a higher risk of later death from cardiovascular disease. This higher risk was independent of which version of the APOE gene the patients had. It was also independent of their lipid levels and other known risk factors such as smoking and diabetes. The strongest relationship between apoE levels and cardiovascular mortality was seen in patients who had low CRP levels at age 85. In most of these patients, CRP levels rose in the following years, suggesting that high apoE levels come before an increase in inflammation.
What Do These Findings Mean?

In old age, at least, high apoE concentrations in the blood indicate an increased risk of death from cardiovascular disease. The results suggest that the common assumption that apoE has antiatherosclerotic effects and therefore protects against cardiovascular disease is too simple. ApoE levels in the blood might have different effects than apoE in specialized immune cells called macrophages that are involved in atherosclerosis. Only six of the 546 participants were taking lipid-lowering drugs such as statins. This is a much smaller percentage than would be expected under current recommendations in the US and Europe. It is not clear whether the same results would have been found if more of the patients had been taking other lipid-lowering drugs, so more research is needed to study whether the observed relationship also holds for persons on lipid-lowering medication.

[rep]

Rep I can see it on the library database but it keeps timing out. I'll try again tomorrow.

Thank you Stavia. I would sincerely appreciate it more than you know. That 2011 study states that rs449647 was studied but within the abstract it's not mentioned again. I would think that the 2011 study with over 1000 people studied is more valid than the 2009 study with under 200 people.

BTW I had to get my rs405509 result from Ancestry because 23andme didn't give one for it.

[Gilgamesh]

More head spinning:

Indeed! Thanks, Richard, and to the others for these interesting articles.

Rep, you must have been sequenced on the V4 chip. Rs405509 is sequenced by the V3 chip.

Did you find out which variants mean what?

I need to get back to work, but there are several papers dealing with these promoters. I think this is potentially very useful info, so I will try to look into it again next weekend.

GB

P.S. This full text is avail.:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986491/

[RichardS]

I find the notion of the plamsa APOE levels being independently predictive quite fascinating.

If you think about it, an independent variable like apoe genotype is present 100% of the time for a given individual. That represents an ongoing influence on health. The apoe levels do vary, so the fact that they found something significant here, I find potentially profound.

What if it is those modifiable lifestyle factors that have significant impacts on apoe levels that are responsible for a good portion of the added E4 risk from things like smoking, excessive alcohol, obesity/diabetes, lack of exercise, etc.? On a brief initial look into the literature, I did not find studies assessing plasma apoe levels as a function of these lifestyle factors, but I would not be surprised to see them with a more comprehensive search. Perhaps this is the real future for tracking risk biomarkers.

[Stavia]

Rep I can see it on the library database but it keeps timing out. I'll try again tomorrow.

Thank you Stavia. I would sincerely appreciate it more than you know. That 2011 study states that rs449647 was studied but within the abstract it's not mentioned again. I would think that the 2011 study with over 1000 people studied is more valid than the 2009 study with under 200 people.

BTW I had to get my rs405509 result from Ancestry because 23andme didn't give one for it.

Rep I cant get it, it just won't load
So sorry.
You can try PM Richard S and see if he can get it for you

[Gilgamesh]

Here it is, plus a response:

An APOE Haplotype Associated with Decreased epsilon-4 Expression Increases the Risk of Late Onset Alzheimer's Disease.pdf

GB

Moderator note - I deleted the attached paper (DOI 10.3233/JAD-2010-101764) because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper there.

[rep]

Thank you Gilgamesh. Now I need to try to decipher them. I don't understand the cis business.

[Gilgamesh]

The "cis" stuff is another sciency weird use of language. Here, they just mean nearby.

But that doesn't matter much in this case, since Rs405509 seems to be inherited fairly independently of the two APOE-defining SNPs.

Looking at figure 2, I realize I need to figure out how the heck to increase apoE levels....

I find the notion of the plamsa APOE levels being independently predictive quite fascinating.

Indeed! We have to remember that our version of apoE isn't always configured in a dysfunctional shape. It's more a statistical phenomenon: large molecules are always shifting shape, and our apoE is just more likely have a shape that makes it unable to do its job well (or, at least, some of its jobs). But at any given time, a certain percentage of our apoE will be working fine, so the more apoE we have overall, the better, one might reason. (Unless the bad conformation has negative effects that are worse overall than the positive effects of the good conformation.)

GB

[Julie G]

I totally bombed on the apoE promoter genes, but still feel somewhat “safe” (any port in a storm ) because I lucked out on the ABCA1 transporter genes that seem to play an integral role with apoE levels in the brain- where it matters. Remember this old paper that James shared with us months ago? It deeply delves into apoE in the brain. I’m too preoccupied with other things right now to really dive into this, but for anyone bummed with their apoE promoter SNPs...this may provide some comfort.

HDL and cholesterol handling in the brain
http://cardiovascres.oxfordjournals.org ... 3/405.long