MUST READ for 3/4 carriers!

[Julie G]

Here’s a fascinating and very significant new paper by Reiman & Caselli et al examining APOE levels and more in 3/4 carriers. I need to read a second time, but my takeaway is that I’d much rather be a 3/4 than a 4/4 .

Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism
https://alzres.biomedcentral.com/articl ... 016-0231-9

Per this paper, E3, but not E4 is responsible for higher overall APOE levels that have been found to be neuroprotective. Higher peripheral APOE was associated with improved cerebral glucose utilization, increased grey matter volume, and weakly associated with improved cognition, the latter not surprising given that cognitive decline would have excluded participation from this study and this was a one time assessment as opposed to a longitudinal perspective.

As many of us have suspected higher LDL is associated with increased APOE in this data set, but that LDL was primarily driven by E3. This seriously calls into question a low fat dietary approach for AD prevention for 3/4 carriers trying to prevent AD.

I would really love to see this work repeated on a 4/4 dataset. Reiman & Caselli probably already have the data given their longitudinal work with an E4 population. Rasmussen’s work (much larger dataset over a long period of time) has demonstrated that higher peripheral APOE levels protected against conversion to AD even among E4 carriers.

[Hepoberman]

Since we 4's have lower levels of circulating APOE (probably due to proteolytic cleavage), It seems to me that lowering the need for higher levels of APOE would be a reasonable approach. APOE is used in the metabolism fat and cholesterol. If you have less fat and cholesterol in your system, the need for APOE is less.

You could do the opposite by adding fat and cholesterol to your system (up-regulating APOE) but elevated LDL carries its own set of risks. It seems pretty straight forward to assume that our best bet is to reduce the trouble caused by our impaired pathways via limiting substrate.

[Julie G]

Did you read the paper? Or Rasmussen's? When put to the test your theory doesn't seem to hold up.

[MAC]

Fascinating, I did not know that we had differing ratios of E4/E3 in our plasma! Apoe4 comprises at most about 25% of total plasma Apoe (both AD and normal cognitive controls).

If you look at the graphical results, there are 2 persons that have apoe3 levels at about 120, whereas the average is about 30!? See image below circled points. What is unique about these persons? But they weren't highlighted in the study for any particular unique cerebral scan? Clearly, there are those persons that have much higher levels of apoe3 than the average of the group, and then some real high outliers. They should perhaps be further characterized by other markers, and at a minimum, followed longitudinally.

Screen Shot 2017-02-03 at 9.14.32 AM.png

Over 80% of this E3/E4 only cohort had dementia in family history, huge hereditary correlation.

"Exactly how the relative ratio of apoE4 over apoE3 isoform levels in plasma can be related to the described structural and metabolic differences in the brain is not clear and linking peripheral apoE levels to processes in the brain is controversial because peripheral apoE does not cross the blood–brain barrier (BBB)"

But is it the ABSOLUTE level of apoe that really matters or the expression of each allele? For some reason, as you move from e2/e3 to e4/4, the ABSOLUTE level of apoe drops rather consistently. Rasmussen showed in a very large study that dementia was inversely associated most strongly with total apoe level, REGARDLESS of genotype. E2/E4 have MUCH lower risk and much higher apoe levels than E3/E4, so is it the E4 allele that's REALLY causative. Or does it really come down to simple lack of lipid metabolism capacity due to insufficient apoe in the plasma....and/or far more importantly, IN THE BRAIN? Seems each higher allele is somehow underproduced or overdegraded leading to lower total apoe? Is the BBB that impervious or is it in fact leaky for this critical system? So if the brain also has low apoe, then over the course of a lifetime, simple lack of regulatory capacity of insufficient apoe leads to nuerodegenerative disease?

Screen Shot 2017-02-03 at 9.27.11 AM.png

Screen Shot 2017-02-03 at 9.26.38 AM.png

From current paper "It has been shown that the turnover rate differs between different apoE isoforms in plasma, with the apoE4 turnover rate almost 4-fold faster than that for apoE2 in APOE ε2/ε4 individuals [31]. As discussed before [33], it is not clear whether the apoE4 isoform levels result from fast degradation paralleled by a lack of compensatory upregulation of apoE4 synthesis or whether the synthesis of apoE4 per se is lower than that of other apoE isoforms due to differences at the expression and/or translation level in the periphery. Given our current results and previous results of a specific reduction in the apoE4 isoform in APOE heterozygous individuals [33], further studies are necessary to confirm that the reported differences are not due to alterations in the allele-specific expression of apoE."

[Russ]

Julie, Excellent find. Finally some evidence that starts to bring some sense and consistency. That said, I, too, would be very curious to learn more about the outliers MAC noted. They are so very anomalous, and seem like they might yield further clues about what conditions can drive APOE levels so high? Interesting to see this team and others built on this research.

[circular]

I look forward to time to digest this. MAC, I like reading your input in discussions, but I was wondering, could you use bold instead of red for emphasis? I have visual contrast issues and glare sensitivity and I find it hard to read the red text. A word here and there isn't an issue, but full sentences are. Sorry, I know that's not something most people would need to think about.

[Julie G]

You bring up a couple of excellent points, MAC. First, (and especially relevant to our 3/4 members) what is so unique about the two outliers? There are an additional handful with levels around 70. Do they share the same traits as those two? Dr. Reiman likely has that information. I've previously spoken with him and plan to reach out to find answers. I'm also going to push for a similar study on homozygotes. He's been doing longitudinal work with an E4 rich dataset for decades and may have the information; just never looked at the correlations.

E2/E4 have MUCH lower risk and much higher apoe levels than E3/E4, so is it the E4 allele that's REALLY causative?

Interesting question. When I look into the risk between 2/4 and 3/4, per data from ADDF, it's not that different; but the levels of APOE are much higher in the 2/4 dataset. So, it's clearly not APOE levels alone that tell the whole story. That being said, if higher peripheral levels help 3/4 carriers and even 4/4 carriers, this is another easy biomarker we can track and tweak.

risk_pic1.png

[MAC]

Julie,

I beg to differ re e2/e4 vs. e3/e4 risk. The ADDF table you attached, what is the study reference?

The vast majority of studies I've seen, the risk of AD is much higher e3/e4 vs. e2/e4. I list below 3 references/graphs, and several other references (I had many many more but did not post tables), as the software does not allow me to post > 3 graphics. The data is very DEFINITIVE showing significantly higher AD risk in e3/e4 vs. e2/e4, which I find a FASCINATING "fact"

In the Reiman & Caselli referenced study, the level of E4 was pretty constant amongst the cohort, but persons had wildly different apoe3 levels? In the Rasmussen Danish large cohort study, IF you assume the population had similar low E4 levels (why not based on the Reiman & Caselli study and E4 turnover dynamics), then the key differential between the risk level was ALL about the level of non-E4 apoe per dose. That is, E2's had MUCH higher apoe2 > apoe3 > apoe4. This is hugely compelling data re apoe plasma level being a more significant driver of risk.

E2/E2 NEVER get AD and they have by far the highest apoe levels?! We're talking about THE cholesterol/lipid lipoprotein carrier in the brain.

What we really need is a CSF apoe dataset by genotype. This is truly root cause work these folks are undertaking.

Re your comment "That being said, if higher peripheral levels help 3/4 carriers and even 4/4 carriers, this is another easy biomarker we can track and tweak." What do you mean by tweak? Are you referring to a way to somehow express /up-regulate your genes to produce MORE non E4 apoe? The answer to that could be the cure to AD? Where do I sign up!

http://www.nature.com/mp/journal/v16/n9 ... 01152a.pdf

Screen Shot 2017-01-28 at 9.48.53 AM.png

https://www.dovepress.com/cr_data/artic ... 6-TS01.png

Screen Shot 2017-02-03 at 11.02.35 PM.png

https://www.researchgate.net/publicatio ... prevention

Screen Shot 2017-02-03 at 11.06.17 PM.png

http://www.google.com/patents/WO1994009155A1?cl=en

http://jamanetwork.com/journals/jama/fullarticle/187321

http://www.scielo.br/scielo.php?script= ... 1000100004

[Julie G]

I beg to differ re e2/e4 vs. e3/e4 risk. The ADDF table you attached, what is the study reference?

No idea, they don't have it listed. ADDF's page was the first 2/4 vs. 3/4 risk assessment I could find. Looking at your evidence, I agree that risk assessment is all over the place and could be considerably higher for 3/4s. I'm intrigued and will look for more up-to-date info.

In the Rasmussen Danish large cohort study, IF you assume the population had similar low E4 levels (why not based on the Reiman & Caselli study and E4 turnover dynamics), then the key differential between the risk level was ALL about the level of non-E4 apoe per dose. That is, E2's had MUCH higher apoe2 > apoe3 > apoe4. This is hugely compelling data re apoe plasma level being a more significant driver of risk.

How can a 4/4 have non-E4 APOE? As you'll recall from Rasmussen, even 4/4s were protected with higher levels. From a 3/4 perspective, based upon Reiman's work, my goal would be to raise non-E4 APOE, but homozygotes don't have that luxury. From our vantage point, based upon Rasmussen's work, the goal may simply be to raise overall APOE. This is why I desperately want Reiman to repeat his current study with a 4/4 population.

Re your comment "That being said, if higher peripheral levels help 3/4 carriers and even 4/4 carriers, this is another easy biomarker we can track and tweak." What do you mean by tweak? Are you referring to a way to somehow express /up-regulate your genes to produce MORE non E4 apoe? The answer to that could be the cure to AD? Where do I sign up!

The answer may lie in Reiman's paper:

Total apoE levels were positively associated with total plasma cholesterol levels (Spearman’s ρ = 0.6552, p = 0.0005) and this association was driven by the apoE3 isoform levels (Spearman’s ρ = 0.6744, p = 0.0003). Total plasma apoE levels were also positively related to plasma LDL cholesterol levels (Spearman’s ρ = 0.4319, p = 0.0351), which is similar to the link between apoE and total cholesterol driven by apoE3 levels (Spearman’s ρ = 0.4806, p = 0.0174). We found no statistically significant associations between apoE4 isoform levels and any of the plasma lipids.

Higher TC and LDL were positively associated with non-E4 APOE. (Bear in mind that LDL-P and ApoB still pose the same CVD risk and the goal may be to raise LDL-C while keeping those levels low.) Also, remember that Thumperama previously reported APOE levels are currently being tested with some of the major advanced lipid testing facilities, but not reported . Until APOE testing is widely available, tracking TC & LDL-C may be helpful. For 3/4 carriers, this certainly would steer me away from purposefully driving down LDL-C.

[circular]

I think I'll send a link to this thread to Rhonda Patrick in case she doesn't spend time here. I think she'd be fascinated and a good one to help follow this and maybe eventually do a podcast after researching it. Not that she knows me from a hole in the wall or that I don't value your input here - keep it coming!

Julie I'd be worried about trying to raise output of apoe in 4/4 through higher cholesterol because if the apoe molecule produced isn't shaped right maybe raising its levels could cause issues?

I wonder if eventually there will be developed an exogenous apoe that's bioidentical to the apoe2 or 3 version (not soon enough sadly).

I also wonder if there are compensatory pathways with respect to apoe's function that help explain why some 4/4s don't get AD even though they must have low apoe levels. Or maybe something enhances their apoe expression and the shape doesn't matter as long as it's cranking.

I better stop, I haven't even read the article or had my morning coffee yet.