Plasmalogens- exciting new evidence

[Stavia]

hi members
Julie, Marc and myself recently met with Dr Dayan Goodenowe, a scientist working in the field of plasmalogens. These are a special kind of phospholipid in the membrane of cells, especially abundant in neural tissue. To actually think, we need to release acetyl choline from little vesicles in the presynaptic neurone. A stiff membrane impedes this process, and a fluid membrane facilitates it. The more plasmalogens in the membrane, the more fluid it is and the better the acetylcholine is released. He has post mortem and human studies which show impressive correlation between plasmalogen levels and dementia, even in e4s. The higher plasmalogen levels attenuate significantly the effect of our e4 allele.
there are as yet no lifestyle interventions we can confidently say raise plasmalogen levels, but it will be available as a medical food in the future.

Here is his power point, and my notes. I didn't fully understand his few slides on lipids and e4s, I will contact him to explain and I will relay this to our community.

Thoughts?

PLASMALOGENS.docx

Prodrome Public AD Lecture plus APOE.pdf

[Harrison]

Thanks Stavia! Very Interesting!

When you contact him, can you get a bit more information about what "metabotypes" PLS1, PLS2, and PLS3 actually represent. A description of that seems to be missing from the slides.

My basic take home message is that his hypothesis fits with the epidemiology. About 60% of AD patients have E4, while it accounts for 25% of the population.

He has E4 with Pls1, Pls2, or Pls3 accounting for 44% of AD cases on slide 72. He has E2/E3 accounting for 36%. (Not sure where other 20% went!). AD is mostly ApoE4 with Pls2 or Pls3, or ApoE3 with Pls3. ApoE4 shifts the risk, but if you can be in the category of Pls1, you are essentially the same risk as an E3 with Pls2.

On a separate note, I find some of the context a bit odd. It goes out of the way to say ApoE4 is only contributing to amyloid and that is not important for cognition, compared to tau. However, the mechanism of plasmologens is mostly tied to amyloid, but he also tries to tie it to cognition. I have noticed a lot of papers trying to down play the role of ApoE4 in AD. I am of mixed emotions about this. On the one hand, it means we are all at less risk (Yay!). On the other hand, researchers are using it as a political maneuver to say why their area of interest should be research should be funded, as opposed to funding ApoE4 research (Boo!).

[NF52]

Hi Stavia,
I did a quick check of Clinicaltrials.gov using several search terms and found no study under the terms "plasmalogens", "Prodrome" or anything like it at U. Penn. Maybe you could ask Dr. Goodenowe to send you the Clinical Trials ID once it's posted. (Given the time delays between when trials are "scheduled" to start and when they actually do, I'm not questioning that it will happen.)
Is it possible to also ask what his views are of the likely efficacy of the current trials for BACE-1 inhibitors, since his slides shows the importance of β-Secretase tied to Flotillin? It suggests that he views BACE-1 inhibition as a downstream intervention which would be unnecessary if we could affect plasmalogens. But if the science is years away from showing that, wouldn't BACE-1 inhibition be useful?

[Searcher]

The higher plasmalogen levels attenuate significantly the effect of our e4 allele.
there are as yet no lifestyle interventions we can confidently say raise plasmalogen levels, but it will be available as a medical food in the future.

Thanks for reporting, Stavia.

Plasmalogens are available in shark liver oil and krill oil. Good idea to take one of those regularly.

"Plasmalogen precursors include omega-3 and omega-6 polyunsaturated fatty acids. At the sn-2 position, plasmalogens are enriched in polyunsaturated fatty acids, specifically docosahexaenoic, C22:6 ω−3 (DHA), or arachidonic acid, C20:4 ω−6 (AA)." So, good idea to eat more polyunsaturated fats, such as in oily fish and nuts.

Egg yolks have arachidonic acid, but an overdose of that increases inflammation and becomes counter-productive. Arachidonic acid can be synthesized in the body from linoleic acid, which is abundant in vegetable oils (including olive oil).

Plasmalogens and their association with AD have been recognized for some time now. See

https://doi.org/10.1007/s00401-011-0836-9

More about plasmalogens:

https://www.sciencedirect.com/science/a ... 160#bb0630

[Stavia]

The higher plasmalogen levels attenuate significantly the effect of our e4 allele.
there are as yet no lifestyle interventions we can confidently say raise plasmalogen levels, but it will be available as a medical food in the future.

Egg yolks have arachidonic acid, but an overdose of that increases inflammation and becomes counter-productive.

thanks Searcher. Dayan says they do not exist in their ultimate form in any food, but have to be synthesized. I wonder if the step from high precursors in diet to high ultimate levels has been shown in any studies.

Do you have evidence about this arachidonic acid snippet that I have quoted? I'm very interested.

[rrmolo]

Those slides are down right frightening if you just turned 78 years old! And the ending with hey just a bit of exercise and a good diet will take care of things! Who are we trying to kid? Not for the faint of heart!

[Searcher]

Egg yolks have arachidonic acid, but an overdose of that increases inflammation and becomes counter-productive.

thanks Searcher. Dayan says they do not exist in their ultimate form in any food, but have to be synthesized. I wonder if the step from high precursors in diet to high ultimate levels has been shown in any studies.

Do you have evidence about this arachidonic acid snippet that I have quoted? I'm very interested.

An example: https://www.ncbi.nlm.nih.gov/pubmed/1907059
There'll be more. There's a study somewhere of the number of eggs consumed per week correlated with adverse health outcomes (I recall it went up to quite high numbers of eggs per week).

Shark liver oil and krill oil contain plasmalogens, not just precursors.

[Julie G]

It was an honor to learn about Dayan's work. (Susan & George also attended the presentation.) I was struck by, and he confirmed, the close relationship between peripheral plasma APOE and plasmalogen. Remember Rasmussen's work? Because plasmalogen is a phospholipid, you'll note (Slide #73) the correlation with a specific lipid pattern: High HDL, low TGs, and especially a high HDL/LDL ratio = high plasmalogen levels. So, while we don't have definitive diet/lifesytle interventions that translate to high plasmologen, we can fairly easily work towards raising HDL and lowering TGs. I completely agree with Searcher that a diet rich in choline and DHA (while perhaps not directly synthesized) still gives us the best chance of increasing plasmalogen levels. I would be very hesitant, especially as an E4 carrier, to be deficient in either.

It suggests that he views BACE-1 inhibition as a downstream intervention which would be unnecessary if we could affect plasmalogens. But if the science is years away from showing that, wouldn't BACE-1 inhibition be useful?

Good question, NF52. We already have some pretty strong data from autopsies, that high plasmalogen is neuroprotective. Those with high levels died cognitively intact. Those with low levels died with dementia. Dayan never proposed that raising plasmalogen would remediate cognitive decline. Instead, Dayan is proposing preventing dementia by maintaining high levels. His RCT has been fully funded by the Alzheimer's Association. I think he's awaiting final approval. Perhaps then it will show up on Clinical trials.gov?

[slacker]

Because plasmalogen is a phospholipid, you'll note (Slide #73) the correlation with a specific lipid pattern: High HDL, low TGs, and especially a high HDL/LDL ratio = high plasmalogen levels. So, while we don't have definitive diet/lifesytle interventions that translate to high plasmologen, we can fairly easily work towards raising HDL and lowering TGs.

There appears to be an association between high HDL, low TGs, and high HDL/LDL ratio to high plasmalogen levels, but is there a causal relationship or merely an association? Do we know that tinkering with these other lipid markers results in higher plasmalogens? For example, pharmaceuticals designed to raise HDL were not successful in reducing coronary artery disease, despite the belief that those with higher HDL had greater protection. The devil is in the details...

[Julie G]

There appears to be an association between high HDL, low TGs, and high HDL/LDL ratio to high plasmalogen levels, but is there a causal relationship or merely an association?

Correct. It's an association or correlation.

Do we know that tinkering with these other lipid markers results in higher plasmalogens? For example, pharmaceuticals designed to raise HDL were not successful in reducing coronary artery disease, despite the belief that those with higher HDL had greater protection. The devil is in the details...

Of course, I can't answer your question without concurrently testing pre & post plasmalogen levels correlated with lipid changes. That said, I'm not sure that your analogy works. HDL-raising Pharma HAS previously failed to affect CAD risk/progression, but I'm suggesting using the old-fashioned method of diet and exercise to shift lipid markers that strongly correlate with high plasmalogen and inversely correlate with CAD.. Slide #73 tells a powerful story.