New paper by Dr. Bredesen & team

[Julie G]

Dr. Bredesen has given me a copy of full-text with permission to share with the community, but for fear of a Digital Millennium Copyright Infringement, I’ll instead direct you to SciHub for those who live in jurisdictions where’s it's legal.

Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease
https://www.ncbi.nlm.nih.gov/pubmed/28879423

Abstract The major genetic risk factor for sporadic Alzheimer’s disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the pu- tative transcriptional role of ApoE4 and propose a mod- el of Alzheimer’s disease that focuses on the transcrip- tional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease.

The authors make a strong case for E4 carriers to upregulate SirT1 to protect against both aging and Alzheimer's. Self-Hacked has a good recent article on the topic: SirT1: Its Role In Chronic Health Issues and How to Increase and Decrease It

[Brian4]

Julie, thanks for this. I don't see any replies to your thread yet, perhaps because people, like me, are too stunned by the brilliance of the paper to get their jaws off the floor.

The implications, if the thesis is correct that a significant negative effect of apoE4 is its transcriptional function, are enormous.

<> As you note, we need to increase Sirtuin1 expression (and possibly the expression of other sirtuins) – if we can (we might have difficulty there, too).

<> We need to slow aging itself as much as possible, in part not simply because aging diminishes Sirtuin1 expression, but also because it dramatically diminishes levels of one of the substrates needed by Sirtiun1, NAD.

<> We need to increase NAD levels if we're over 40 or so (via NR, NMN, or NAD+ infusions, for ex.).

<> More fundamentally, I'd say, given the numerous other possible transcriptional roles of apoE, we should support the work underway now to create small molecule correctors. ApoE4 just seems like such a bad isoform of apoE that the easiest thing to do would be to turn into it apoE3....

Thanks again,
Brian

[Julie G]

Agreed, Brian. I found this pretty profound. Simple really, all we need to do to prevent AD is to stop aging . I assume NR is nicotinamide riboside. (Please correct me if I'm wrong.) What's NMN? What path are you taking?

[circular]

Agreed, Brian. I found this pretty profound. Simple really, all we need to do to prevent AD is to stop aging

So what's taking us so long?

[Brian4]

Apologies for all the initialisms.

NR --- nicotinamide riboside
NMN --- nicotinamide mononucleotide
NAD+ --- nicotinamide adenine dinucleotide

My strategy has been undergoing lots of revisions. Main components that are most directly related to sirtuins and NAD (I'll post later, elsewhere, about other components), for now, are:

- Various forms of restricted eating (very low carb (nearly 80% calories from fat) six days a week, periodic near-0-calorie fasting days).
- Exercise aerobically after every meal – usually long, and not too intense.
- Take 500 mg metformin with the rare meal that can't be followed by exercise (couple times a week, max). Considering using berberine instead.
- Take 250–500 mg of NR. (Haven't made up my mind about right dosage....)

So much research is going on now that one almost has to be on one's toes, and ready to shift strategies at a moment's notice.

Brian

[rrao2015]

Thanks for all the good words about our work. It's sad that not many in the field will appreciate the transcriptional function of ApoE4. It is interesting, when physicists/mathematicians/chemists see an evidence based work, they will support the findings. Not so with biologists. If it does not fit their model, they will cry out loud "we don't believe the work". This is what is happening with our work. But we will move on...

Nicotinamide Riboside is a good supplement to take to boost the NAD levels

[circular]

Thanks for all you're doing rrao! We are listening and word will get around!

[circular]

BTW Julie and Brian, for the life of me I can't figure out how to get full access through SciHub?

[Sandy57]

Great paper, but how does it apply to a 3/3? If at all.
Frank

[l2silver]

Very interesting stuff.