Ketones may not improve regional cerebral blood flow in E4

[Kenny4/4]

I agree that ketones and ketosis may still be a valid tool for preventing or helping assuage MCI and Alzheimer's symptoms in E4's . The title should read -
Ketones may not improve regional cerebral blood flow in E4 that are being fed a typical carbohydrate diet

What would happen on a low or no carb diet?

A quote from the case study Julie cited -

Recent research demonstrates that insulin defect competes for space with APOE4 in brain cells, thus exacerbating amyloid pathology (Zhao et al., 2017).

As stated on this site by many -"keeping insulin in check is very important in possibly preventing Alzheimer's".

A higher carbohydrate diet typically yields more insulin which requires more IDE insulin degrading enzyme. IDE is also used to help clear amyloid so the train of thought says if we are using IDE for degrading insulin we aren't using it to clear amyloid. True ? False?
If APOE 4's produce 40% less IDE as I have read wouldn't we be handicapped in clearing amyloid compared to non APOE4's in a high carbohydrate enviroment ? I have read that IDE has different phases and can be doing different tasks according to what phase it's in.
It was unclear how it all really works and if the train of thought I have above is true. Does anybody know how all that really works biologically - mechanistically ?

I keep coming back to the anthropology of APOE4 and that it is highest in frequency in low-carb populations such as Inuit, Sami, San (bushmen of the Kalahari) . The Nigerians may have a high fat diet as well as they eat a lot of palm oil. How much I don't know?

I don't think people can write off Ketones and Ketosis just yet.

[apod]

As stated on this site by many -"keeping insulin in check is very important in possibly preventing Alzheimer's"

And if keeping insulin in check involves keeping carbohydrate intake in check... to what extent does this apply to keeping protein intake in check? Ah, these studies always raise more questions than they answer.

[Kenny4/4]

As stated on this site by many -"keeping insulin in check is very important in possibly preventing Alzheimer's"

And if keeping insulin in check involves keeping carbohydrate intake in check... to what extent does this apply to keeping protein intake in check? Ah, these studies always raise more questions than they answer.

I don't know.. yet?
Insulin is released when protein is eaten that is for sure. I believe it is about 60% of what carbs are. That would fit nicely with a 40% less IDE (Insulin Degrading Enzyme) that us APOE4's exhibit. There is a previous thread that talks about Insulin and Glucagon ratios, it could tie into this nicely viewtopic.php?f=4&t=4625&hilit=Glucagon .

[cflegal]

Interesting article James.
Excuse my ignorance; is cerebral blood flow the best marker to determine that ketones (or glucose for that matter) are crossing the blood brain barrier and getting to brain cells?
And were blood ketones levels measured to determine level of ketosis? Were ApoE4 ketone levels lower than non ApoE4s?

The source article refers to this as a "pilot study", with most of the 6 authors from the "Translational Imaging Division" of Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA. The entire report is very short, without the sort of details, including how many were ApoE 4, that you're asking about. My perhaps unfounded hope is that they had either a population-based percentage (about 25%) or higher representation of 4's. I would assume that as a "pilot", this could now be used to seek a much higher level of funding by the NIH or others for a bigger study. The numbers here could change completely with a larger sample size; however, the double-blinded, one variable (ketone) design and pre-and-post PET scans all were designed to demonstrate an early "test of concept" I imagine.

This is not the first confusing article relating to the use of Axona (caprylidine) in a research study. This was a very, very small short 45 day study involving 14 subjects mixed between mild to moderate AD. I don't see anyway to extrapolate the results to anything of interest to me.

[mike]

Just anecdotally, I took exogenous ketones for a week, and I found it did give cognitive clarity, but I noticed my fasting blood sugar began to go up. Not supposed to happen...

[TheresaB]

First, I didn't think the purpose of ketosis was to improve cerebral blood flow. Other benefits for the brain, certainly, but cerebral blood flow, no, at least not with what I've read.

Just anecdotally, I took exogenous ketones for a week, and I found it did give cognitive clarity, but I noticed my fasting blood sugar began to go up. Not supposed to happen...

Interesting. And in an interview with Dr Rhonda Patrick, (Joe Rogan Experience #1178 at about 1:54:30 mark) , Dr. Patrick said she found using an exogenous BHB ester gave her energy, made her less anxious, and sharpened her mental processing, but she went on to say that after a couple hours the exogenous ketones wore off, her blood sugar lowered and she would crash. She said this was because she doesn't follow a ketogenic diet so her body didn't produce ketones to compensate. Another mark for endogenously producing ketones.

[Fiver]

I've been reading about a second potential effect of ketones on the brain (in addition to their use as an alternative fuel). It seems that ketones are fairly good HDACi's - that is, substances that "wake up" genes that were put down for a nap in the nucleus.

But I overlooked a basic question. How much of these ketones enter the brain? there are several different ketones in the blood during ketosis and also several other closely related compounds that come from the microbial digestion of leafy greens and fibers. I was surprised to find the some of the leaf green products didn't pass the blood brain barrier very well at all.

Anyone know off the top of their head? thx

[mike]

I've been reading about a second potential effect of ketones on the brain (in addition to their use as an alternative fuel). It seems that ketones are fairly good HDACi's - that is, substances that "wake up" genes that were put down for a nap in the nucleus.

But I overlooked a basic question. How much of these ketones enter the brain? there are several different ketones in the blood during ketosis and also several other closely related compounds that come from the microbial digestion of leafy greens and fibers. I was surprised to find the some of the leaf green products didn't pass the blood brain barrier very well at all.

Anyone know off the top of their head? thx

Ketone Bodies (like BHB) can cross the BBB and then be used by the mitochondria in neurons as fuel.

https://blogs.scientificamerican.com/mi ... antageous/

A ketogenic diet also increases the number of mitochondria, so called “energy factories” in brain cells. A recent study found enhanced expression of genes encoding for mitochondrial enzymes and energy metabolism in the hippocampus, a part of the brain important for learning and memory.

Also, the higher ketones seem to inhibit production of oxidants.

[mike]

Here is another interesting article discussing how a keto diet can help repair the BBB...

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

Prolonged exposure of BBB endothelial cells to KBs induce expression of monocarboxylate transporters and enhances brain uptake rate of KBs. In addition, cell migration and expression of gap junction proteins are upregulated by KBs. Altogether, these reports suggest that the beneficial effects of the ketogenic diet may depend on increased brain uptake of KBs to match metabolic demand and repair of a disrupted blood-brain barrier (BBB). As the effects of KBs on the BBB and its transport mechanisms across the BBB are better understood, it will be possible to develop alternative strategies to optimize its therapeutic benefits for brain disorders where the BBB is compromised.

[Fiver]

Thanks Mike. I was reading this: http://www.academia.edu/26738579/The_ne ... brain_axis. The article discusses butyrate - which is formed from microbial digestion of plant material in the digestive system. This molecular apparently doesn't get far. Most of it feeds the gut lining cells. The paper implies that it doesn't reach the brain since radiolabelling studies show only a tiny portion butyrate was found inside the brain. But later they say it can reach and stabilize the BBB and be imported via pumps (but perhaps not when NSAIDs are used; they block the necessary pumps it seems). But levels in the blood and near the CNS are very low, even when people or animals eat loads of veggies and have the best butyrate-prioducing microbes. So I was unclear about that. It seems to be a yes in theory, probably not in practice sort of thing (unless applied exogenously at higher levels, which is a common medical research approach to some chronic diseases).

It is a close cousin of the beta hydroxy butyrate that is one of the ketone bodies produced during ketosis. I found that interesting.

Both seem to be potential alternative fuels. Both acts as HDAC inhibitors - which "wake up" napping genes and generally have positive effects. (Other natural HDACis include some familiar plant substances sometimes discussed here, by conicidence.)

A lot of what we try to do acts to promote HDAC activity. So I'm thinking that either plant fermentation to butyrate or ketogenic formation of beta hydroxy butyrate alone might be a little "good", but both together could be significantly better. Which is really only me slowly catching on and understanding what is in the wiki here... Yes, I'm slow.

So basically ketogenic diets and eating lots of leafy greens would work well together, which we already knew.

I've no read anything about blood flow, however.