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

[Russ]

Another new jewel from Dayspring's tweet stream on just published paper he calls "Major News":

A

nn Neurol. 2015 Feb;77(2):301-11. doi: 10.1002/ana.24326. Epub 2015 Jan 13.
Plasma levels of apolipoprotein E and risk of dementia in the general population.
Rasmussen KL1, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R.
Author information
Abstract
OBJECTIVE:
The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis.
METHODS:
Using 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype.
RESULTS:
Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends < 1 × 10(-6) ). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval [CI] = 2.04-3.52) and 1.80 (95% CI = 1.52-2.13) for Alzheimer disease and all dementia, respectively. After further adjustment for ε2/ε3/ε4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend = 0.007) and all dementia (p for trend = 0.04). Plasma apoE tertiles did not interact with ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease (p = 0.53) or all dementia (p = 0.79). In a subanalysis, the -219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype (HR = 1.56, 95% CI = 1.05-2.30).
INTERPRETATION:
Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype. This is clinically relevant, because no plasma biomarkers are currently implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker. Ann Neurol 2015;77:301-311.
© 2014 American Neurological Association.

http://www.ncbi.nlm.nih.gov/pubmed/25469919

Will make time to read this one if someone has access....

[Stavia]

here you go

ana24326.pdf

Moderator note - I deleted the attached paper (DOI: 10.1002/ana.24326) 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.

[Julie G]

This does feel like BIG news. Dayspring is hot on our case. Thank you, Russ and Stavia

As always, I look at these predictive biomarkers to see if they are modifiable. At first glance, this seems to corroborate Federoff's paper last spring that found a deficiency in serum lipids preceded AD. When questioned, he admitted they had not accounted for statin use in their study.

We know that lipophilic statins reduce serum APOE. Does anyone know if that's true for non-lipophilic statins?

Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia
http://www.jlr.org/content/43/9/1464.full

Are there ways we can increase serum APOE levels?

[karelena]

"Furthermore, it does not seem likely that the e4 risk increasing
effect is explained by its association with lower
plasma apoE levels, because e44 versus e33 is associated
with an 8-fold risk of Alzheimer disease but only a
1mg/dL lower apoE level, whereas lowest versus highest
apoE tertile is associated with a 3-fold risk and a 3mg/
dL lower apoE level."

Hi, I'm new to post here although I've been reading your forum for a while. This article seems to show that even when you account for the increased risk due to genotype, there is an additional risk when APOE is at the lowest tertile. Which is interesting because they also show what appears to be an association with the highest APOE levels for the genotype e22 and lowest for e44.

"e2/e3/e4 APOE genotype was associated with stepwise
decreases in plasma levels of apoE of up to -65%
e42 to e33 to e43 to e44 (Fig 2, left panel)."

So the e33s, (who make up 55.8% of their population) have 52% less APOE than the e22s, and the e44s have 65% less so they are saying that is not that big a difference. Yet the e44s still have the biggest risk of AD.

Maybe the e44s just need a little more APOE. Just about 13% more or so.

It would be interesting to see some research on what could possibly raise the APOE serum level or if enzyme replacement would affect the development of AD.

Thank you to the founders and contributors for this site. It is sometimes a scary place to visit (to face the sad truth about e44) but it is nice to have a community and know others are searching for answers and continue to hold on to hope for a cure.
K

[Tincup]

Following Julie's thought, a search on "increase APOE levels" https://www.google.com/search?q=non-lip ... poe+levels seems to muddy the picture. Don't have time to read all right now - just a quick scan.

[Julie G]

Welcome karelena! We want to be a warm and welcoming community; not a scary place. Trust me, I do understand what you're saying. The APOE-ε4 allele CAN be frightening to read about. Hopefully, by learning together, we can employ lifestyle strategies that reduce our risk.

Head spinning, George I'm trying to learn more in the middle of a busy day... I'm far from grasping the implications of this. IF (note caps) this holds true for our population, I'm trying to ascertain ways to increase APOE and/or prevent a reduction. It looks like large HDL particles contain elevated amounts of APOE. Could their presence be indicative of increased APOE?

[rep]

Would someone, anyone, who knows how to interpret these papers be kind enough to put it into plain English and give us the takeaways?

[JulieAnnie]

http://www.ucsf.edu/news/2012/04/11810/ ... alzheimers

A little more confusion for tonight

Recent research by another group found that a drug that boosted apoE protein levels also reversed the build-up of Aß in mice genetically modified to mimic Alzheimer’s. So some scientists have theorized that boosting apoE levels could be beneficial in slowing the disease’s progression in humans, and several groups have begun to explore this therapeutic strategy.

In this study, Huang and his team tested this idea. They genetically modified mice to have either human apoE3 or apoE4 and then monitored them for any subsequent build-up of toxic Abin their brains as they aged.

“We thought a straightforward relationship existed between apoE protein levels and Aß, and that boosting apoE levels in these mice would promote — not halt — the build-up of Aß,” explained Gladstone Postdoctoral Fellow and lead author Nga Bien-Ly, PhD.

The team’s experiments revealed both surprising and intricate roles for apoE. In young mice, apoE proteins produced by all variants of the apoE gene — even the risky apoE4 variant — are essential because the protein they build helps clear away excessive amounts of Aß. But as the mice aged, this process began to malfunction — especially in those mice with two copies of the apoE4 gene but also in mice with two copies of apoE3. As apoE protein levels rose, Abbegan to accumulate. But in mice mutated to have only one copy of the apoE gene — either apoE3 or apoE4 — apoE protein levels dropped by half and Aβ build-up was reduced. These results indicated that Abbuild-up isn’t associated only with a specific apoE variant, but instead is also related to the overall amount of apoE protein produced as the brain ages.

“Our findings suggest that reducing levels of proteins produced by either apoE3 or apoE4 — rather than raising them — could be key to lowering Aß build-up in the brain,” said Huang. “We hope that our research could spur new therapies that successfully combat Alzheimer’s at the molecular level — putting us one step ahead of this deadly disease.”

[Julie G]

I saw that, JulieAnnie; hence the head spinning Has anyone tracked down the three APOE promoter SNPs? I think I did, but I'm uncertain if I've done it correctly. 23andMe only seems to report on two.

FWIW, here's the press release for the paper:

Simple blood test can predict risk of dementia

DEMENTIA Scientists at Rigshopitalet, Herlev Hospital and the University of Copenhagen identify a new biomarker that can predict the risk of developing dementia by way of a simple blood test. In the long term, this could mean better prevention and thus at least postponement of the illness and at best evading the development all together. The study was recently published in an internationally acclaimed journal, the Annals of Neurology.
Globally, in excess of 35 million people suffer dementia – in Denmark alone, there are approx. 80,000 who suffer this illness. Prevalence increases in step with aging, and as people’s life years are continually on the rise in most countries, there is also an increasing need to be able to identify the citizens who are at the greatest risk of suffering dementia.

As opposed to cardiovascular diseases, where the level of cholesterol in our blood indicates the risk of cardiac arrest, there are no such trustworthy markers in our blood in terms of diagnosing the risk of dementia setting in. However, Scientists at Rigshopitalet, Herlev Hospital and the University of Copenhagen have now identified a new biomarker, measurable in a simple blood test, which will help predict the onset of dementia.

More precise risk evaluation
"The blood test will help provide a more precise risk evaluation of a citizen’s risk of developing dementia later in life. Thus the citizens at the greatest risk of developing the illness are more easily identified than at present," Ruth Frikke-Schmidt, assistant clinical and research professor at the Faculty of Health and Medical Sciences at the University of Copenhagen and consultant physician at Rigshospitalet, states.

Researchers hope that with time, this new blood test will be applicable in clinical practice. "The blood test will enable an earlier and more focused prevention effort, thus prolonging the onset of the illness and raising the individual’s quality of life," adds Ruth Frikke-Schmidt.

76,000 people partook in public studies
In the study, researchers show that a low level of the biomarker, the so-called apolipoprotein E, in our blood, increases the risk of developing dementia in the future. This was revealed in comprehensive studies of the general public, the Herlev-Østerbro Study and the Østerbro Study, involving 76,000 people.

Point of departure for the development of new drugs
The healthy brain consists of millions of interconnected nerve cells. The brain in a person suffering dementia is very different. The well-organised, structured coordination of nerve cells is intersected by, among other things, senile plaques that consist of the viscous compound, β-amyloid.

The low level of apolipoprotein E in the blood, as the researchers point out in the study, most likely reflects a low level of apolipoprotein E in the brain, and this indicates that the viscous compound, β-amyloid, is less effectively removed. Thus the study’s results underpin a biological mechanism. "Over time, this increased biological knowledge about dementia can constitute a point of departure for the development of new drugs," Ruth Frikke-Schmidt concludes.

[rep]

Please help me out. I'm hoping I am on the right track. I googled apoe promoter and found 2 studies, one from 2009 and one from 2011. Are these SNPs that would affect the serum APOE? I'm a newbie with no biology background so I won't be surprised if I'm way, way off track so please tell me if I am and my feeling will not be hurt. I'm just taking a stab at it.

Based on the 2009 study I'm very concerned about my rs449647 A/A. But then in the 2011 study for which I only have the abstract they focus on the rs405509 G/G, I believe. Does that mean I'm in the clear with my rs449647 A/A?
I need a better brain than mine to figure this out!

Can Stavia or someone please provide access to the full text of the 2011 study?

2011 Study
-491 rs449647 A/A bad per 2009 study. I am A/A. In the conclusion of this study it does not say that is bad.
-219 rs405509 G/G bad. I am A/G, which is good.
This study seems to focus on rs405509 G/G as being bad. I can only access the abstract so I'm left wondering what conclusion they reached about rs449647.

http://www.ncbi.nlm.nih.gov/pubmed/21263195
J Alzheimers Dis. 2011;24(2):235-45. doi: 10.3233/JAD-2011-101764.
An APOE haplotype associated with decreased ε4 expression increases the risk of late onset Alzheimer's disease.
Lescai F1, Chiamenti AM, Codemo A, Pirazzini C, D'Agostino G, Ruaro C, Ghidoni R, Benussi L, Galimberti D, Esposito F, Marchegiani F,Cardelli M, Olivieri F, Nacmias B, Sorbi S, Tagliavini F, Albani D, Martinelli Boneschi F, Binetti G, Santoro A, Forloni G, Scarpini E, Crepaldi G,Gabelli C, Franceschi C.
Author information

Abstract

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and ε rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and ε4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/ε4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclassified.


2009 Study
rs449647 A/A bad. I am A/A, which is bad.
-219 rs405509 G/G bad. I am A/G, which is good.


http://www.ncbi.nlm.nih.gov/pubmed/1917 ... t=Abstract
Eur J Hum Genet. 2009 Jul;17(7):938-45. doi: 10.1038/ejhg.2008.263. Epub 2009 Jan 28.
The complex interaction between APOE promoter and AD: an Italian case-control study.
Bizzarro A1, Seripa D, Acciarri A, Matera MG, Pilotto A, Tiziano FD, Brahe C, Masullo C.
Author information

Abstract
The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be epsilon 4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/epsilon 4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.