new research

[Stavia]

Julie, I think they're stabbing in the dark here. I don't think this work is anywhere near being useful for humans in a practical sense - and not likely to be useful for some years yet. I think its still in the arena of finding out what questions to ask before designing more experiments.

[Harrison]

Trying to increase ApoE lipidation is very reminiscent of Bexarotene’s mechanism of action. Whatever happened to that?
http://www.alzforum.org/news/research-n ... -pathology

Funny you should ask. Not good news I'm afraid. A very small (borderline useless) clinical study was just published:
http://www.ncbi.nlm.nih.gov/pubmed/26822146

They had 20 patients, 16 on drug and 4 placebo. Then they stratified by apoE genotype, so there were 4 apoE4-/-, 6 apoE4+/-, and 6 apoE4+/+. They claim a significant reduction in brain amyloid in ApoE4-/- (this being a comparison of 4 non-carriers on Bexarotene vs. 3 non-carriers on placebo). The chances of that being replicated are fairly low in my opinion.

The authors seems to be torn on which route would provide the best Aβ clearance: reducing ApoE or increasing it.

This has been a debate in the apoE field for quite a while. There are firm opinions on both sides. I think it comes down to whether you think apoE4 is a loss-of-function or a toxic gain-of-function.

[circular]

The authors seems to be torn on which route would provide the best Aβ clearance: reducing ApoE or increasing it.

This has been a debate in the apoE field for quite a while. There are firm opinions on both sides. I think it comes down to whether you think apoE4 is a loss-of-function or a toxic gain-of-function.

Ah, geez, and placing bets one way or the other with a high fat diet is, well, gambling?

[Julie G]

Harrison- great find, but huge disappointment. In addition to the very small dataset, they chose patients that were quite severely affected. It’s frustrating to see such little progress when this is already an FDA approved drug that HAS shown early promise in our population… albeit in our furry friends.

Stavia, I completely agree. Gaining anything useful from this paper is a bit like reading tea leaves, but I love looking for clues.

(((Circ)))

[Gilgamesh]

I think it comes down to whether you think apoE4 is a loss-of-function or a toxic gain-of-function.

Harrison, I think that's exactly right. And we really don't know.... (And of course it could be both, in diff. ways.)

Stavia, I wouldn't say stabbing in the dark: they make no claims about providing answers; I read the paper (above all the Discussion section) as trying to clarify the relevant questions, in order to guide future research. (They are reminding us that there is a lot of darkness.) Thus: not stabbing in the dark, but rather trying to map a terrain cloaked in darkness, I'd say. I think they do an excellent job there.

Onward!!
G

[Stavia]

True G. Trying to open up the darkness.
But its still far too premature to try and use this to inform a human diet.

[Julie G]

...I couldn't resist sharing this old chestnut from Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. It's a nice graphic summary of both the ApoE4 loss of function AND toxic gain-of-function

nihms492068f3.gif

[J11]

Hmm, I am seeing this bexarotene trial as a fair success.

Even with only 4 non-carriers in the bexarotene treatment arm and 3 in the placebo arm, they reported significant results of amyloid lowering in nearly every brain region. This was after only 4 weeks of treatment. In fact the first week of treatment was more of a leadin week. In the supplemental write-up they noted that they did not even use the fully equivalent mouse dosing in the study. The original research had found that hitting the right dosing was important. A dosing study could more clearly determine the optimal range.

The patients in the trial had moderate AD. It is widely understood that by this point there is a large buildup of amyloid. Studying pre-symptomatic people might be very helpful.

Bexarotene could already be emerging as an amyloid lowering approach for those who want to proactively manage their AD risk (especially non-4 carriers).

[J11]

Longer term (6 month) Bexarotene treatment at this dosing level (300 mg) improved cognition in an early stage epsilon 3,4 AD patient.
http://www.ncbi.nlm.nih.gov/pubmed/26444777

DHA amplified the effect (in mice).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469742/

[Julie G]

...but then there's this: http://www.sciencemag.org/news/2016/02/ ... wants-know