Htr-A1 - ApoE4 degrading enzyme

[Harrison]

High APOE in CSF associated with AD reflects leaky BBB.
Low APOE in plasma probably reflects low synthesis by astroctes.
Problem with APOE4 is lack function. Therefore if in old age E3 synthesize less will cause less function. In mouse studies APOE null mice same as APOE4 mice.
Decrease APO3 in old age good explanation some risk AD in non-E4 in old age.

Wouldn't low plasma ApoE reflect low synthesis by the liver? And regarding high apoE in CSF, are you suggesting that is not from astrocytes, but rather peripheral apoE crossing the BBB?

ApoE4 loss of function vs. toxic gain of function, at least as far as brain function, has been a debate for 20 years. The recent work by David Holtzman's Lab in mice expressing human apoE crossed with a Tau mutant causing frontal-temporal dementia suggests that ApoE4 may be a toxic gain of function https://www.nature.com/articles/nature24016.

Whether one would want to decrease apoE or increase apoE remains a matter of debate, although the data suggesting low apoE expression is more correlated with disease does suggest lowering might not be the end-all-be-all approach.

[Fiver]

Ugh. Just when you think you understand a little bit about cholesterol metabolism....

I remember this study. But no matter how much I read I can't seem to find a clear answer to the general questions:

Are higher E4 levels better or worse than lower E4 levels? In other words, do E4s benefit from raising or lowering IDL and HDL particle numbers (both include apoE apoproteins)? (Back to the "are statins good" debate, I suppose)

How do we untangle the fact that apoE is a part of "good" and "bad" particles? If an E4 has high HDL is that as much of a "problem" as high IDL?

Why are plasma apoe4 levels related to AD risk is they don't cross the BBB?

...re-reading this.

[alangreenmd]

My comments belong in APOE Plasma levels predict dementia independent of Geneotype discussion and comment in response to Harrison.

[alangreenmd]

On Tau pathology.
AD especially in APOE4 carriers is a 2 hit disease.
There is what APOE4 does in hit 1, degeneration of cerebral microvascular system and breakdown of BBB.
Then there is 2nd hit: amyloid-beta and hyperphosphorylated Tau

All totally different steps and all very interrelated

For best discussion of Tau see papers by JJ Pei, Salvatore Oddo.
Best summary of Tau, see Talboon...Rapamycin at the Crossroads.

Taupathies very interesting collection of neurodegenerative diseases.

This paper show APOE4 toxic function as regards some Tau steps very interesting.
Increased mTOR involved in very many steps involving Tau pathology: increased production Tau, decreased removal by autophagy, increased phosphorylation and decreased pruning by phosphatase.

This one more step; a toxic function of APOE4.

However, since APOE4 primary increased risk for AD and not primary Tauopathies, toxic function of APOE4 in Tau doesn't seem too clinically significant.

[alangreenmd]

AD is like a Jig saw puzzle with 250 pieces; the hard part is you have 1000 pieces in the box. In you look at the research of Berislav Zlokovic, Salvatore Oddo, Patricia Galvan, Ai-Ling Lin, JJ Pei; it all fits together into one very coherent picture, all supported by autopsy finding in human brain and supporting mouse studies. However, there are another 750 pieces as everybody has their own theory.

Pathogenesis is generally accepted when have a cure. So until have documented methods of prevention and treatment, everybody gets to have their own theory.
Right now pathogenesis of AD is understood about as well as most other very complex diseases. What is different about AD is that there are very many competing theories.
The most important thing to know about pathogenesis of AD is 99.6% of treatments tested have been totally unsuccessful. Draw your own conclusions of what the extraordinary failure rate means.

[Julie G]

I stumbled across this blog post from a (non-credible to me) source who claims to have advice on how to increase APOE levels. Interesting, but I'm not certain his conclusions are correct... Thoughts?

[Orangeblossom]

I stumbled across this blog post from a (non-credible to me) source who claims to have advice on how to increase APOE levels. Interesting, but I'm not certain his conclusions are correct... Thoughts?

He says about a high fat diet increasing APOE levels, but the paper he links to says it may be increased in plasma but not in brain. A bit confusing.

[Julie G]

He says about a high fat diet increasing APOE levels, but the paper he links to says it may be increased in plasma but not in brain. A bit confusing.

Good find, but remember per Rasmussen it's the plasma that is correlated with improved cognition.

[Orangeblossom]

He says about a high fat diet increasing APOE levels, but the paper he links to says it may be increased in plasma but not in brain. A bit confusing.

Good find, but remember per Rasmussen it's the plasma that is correlated with improved cognition.

Yes, that's right. And also an interesting difference with ketosis showing significant changes in levels in E4 rather than E3...

"To determine if the effect of the high-fat diet on hippocampal ApoE was purely due to dietary fat, we completed a comparable experiment in mice fed a ketogenic diet. The ketogenic diet, which is high-fat and very-low to no carbohydrate, causes increased energy expenditure and fatty acid oxidation with reduction in lipid synthesis [16]. The role of ApoE and its isoforms in the ketogenic state is relatively unknown. In contrast to the high-fat diet, we found no change in hippocampal ApoE levels in response to ketogenic diet for any genotype. However, we did observe an interesting effect of ketogenic diet on plasma ApoE, with ApoE4 mice having a large increase in plasma ApoE in response to ketosis, while ApoE3 mice experienced a more moderate change."

Link to the paper mentioned here. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734705/

It would be great if we had some similar info on humans and how their levels change in response to diet (brain and plasma)

This was interesting as it was in contrast to the high fat diet which caused a reduction in hippocampal levels in APOE3. It seems perhaps the levels of carbohydrates makes a difference. I note the study is in mice fed high sat fat / lard, so again may be a difference in humans intermittent fasting and ketosis through low carb / primarily monosaturated fats...interesting though the different effects.

With regard to the plasma levels, I guess we need to ask why increased plasma levels are helpful...is it a reflection of levels in the brain, perhaps not as it was not simply correlated with APOE4 types. Does it somehow impact on the brain...similar to how high HDL levels do? Could the two things be related? I'm not sure, I don't know enough about it.

I can see that increasing HDL looks helpful and if increasing plasma levels into the bargain helps too that would be a bonus...

[Orangeblossom]

He says about a high fat diet increasing APOE levels, but the paper he links to says it may be increased in plasma but not in brain. A bit confusing.

Good find, but remember per Rasmussen it's the plasma that is correlated with improved cognition.

Since last posting, I searched and found a slightly more recent paper by Rasmussen which was available in the full text, and had some more info and thought you might find interesting.

It says

"it has been shown that associations between the APOE polymorphism and lipid levels across studies or across subgroups within studies appear to be influenced by gender, diet, alcohol consumption, hyperglycemia, estrogen therapy and possibly body size [30."

I was interested to see that APOE levels rose in women compared to men after around the menopause as well,

"In the ApoEurope project, a sex-differential effect of age on mean levels of apoE was observed [[45], [58]]. In men, the levels of apoE leveled off after the age of 45 years, whereas they continued to increase in women [58. A similar pattern was found in 76,000 individuals from the general population"

Here is the link

Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review
http://www.atherosclerosis-journal.com/ ... X/fulltext