1229 replies to this topic

[ceridwen]

Possibly because Tau is the main problem not amyloid. Not to mention diabetes 3 and inflammation.

[resveratrol_guy]

I don't have the study in front of me, but when I looked at it, the treatment group MMSE was materially and dramatically better than the controls.  Yes, treatment declined slightly, but it was nothing compared to controls.

 

You don't find that compelling?  Just the fact that amyloid is cleared in such a dramatic fashion, which likely has a downstream effect on Tau and ultimately improved MMSE scores, seems extremely compelling to me.

 

I personally wish there was a better answer for removal of Abeta than a monoclonal antibody.  But this drug seems like it could be some kind of legitimate answer, in the absence of any better alternative really.

 

I find aducanumab compelling indeed, but as a monotherapy, it's still a failure. But you're right: in the absence of any superior alternative, I'd be happy to see it made available economically, and ideally recreationally.

 

Still, we have to live in the real world. These results, even assuming that they're reproducible, are clinically irrelevant in Western countries. They'll give the drug too late and it won't serve any purpose other than to prolong suffering, not to mention that it will probably require a lifelong dosing regimen, like nilotinib for Parkinson's, which further diminishes its economic viability.

 

ceridwen is right: misfolded tau is the number one problem. And we need permanent immunity, not a new pharmaceutical drug addiction costing thousands of dollars per month.

 

The science is probably good, and the most important takeaway is that immune manipulation is a viable strategy with a lot of promise, absent something better like gene therapy.

 

If, in middle age, you can find this stuff on the black market and inject yourself sufficiently often to clear your amyloid, it just might help you. But that's easily 10 years down the road, by which time, tau vaccine will have completed stage 3 and China will probably be doing neural tissue grafts.

[ceridwen]

The side effects of the drug are water on the brain and strokes. Meanwhile mega doses of Vitamin C seem to be having a positive effect on my tinnitus but it's not enough when I stop taking it for sleeping or whatever it comes back. Souvenaid did not help but then I have the MTHFR SNP.

[ta5]

Maybe interesting... Kind of an odd article. Oddly worded at least. The link below is to the full article.

 

Aging (Albany NY). 2016 Sep 14.

Targeting therapy for homocysteic acid in the blood represents a potential recovery treatment for cognition in Alzheimer's disease patients.
Hasegawa T1, Ukai W2.
At present, we have no reliable means of recovering cognitive impairment in Alzheimer's disease (AD) patients. We hypothesized that homocysteic acid (HA) in the blood might represent one such pathogen that could be excreted into the urine. Since DHA is known to reduce circulating levels of homocysteine, and since exercise attenuates this effect, it follows that supplementation of the diet with DHA, along with increased levels of physical activity, may help to reduce cognitive impairment in AD patients. Our hypothesis was proven to be correct because memory problems in 3xTg- AD mice (a model for AD in which animals develop amyloid pathology), and in a mouse model of familial AD, were recovered following treatment with an anti-HA antibody and not by amyloid treatment. Interestingly, 3xTg-AD mice with amyloid pathology showed increased levels of HA level. This could perhaps be explained by the fact that amyloid precursor protein and/or presenilin increases calcium influx, which could then increase levels of superoxide and consequently increase levels of HA from homocysteine or methionine. Our hypothesis is also partially supported by an open clinical trial of certain dietary supplements that has shown impressive results. Also there are other treatments hypothesis which would be possible for the effective therapies, such as ribonucleoprotein therapy, a β-secretase inhibitor treatment and the metabolic enhancement treatment.
PMID: 27632569

[Der Springende Punkt]

Maybe interesting... Kind of an odd article. Oddly worded at least. The link below is to the full article.

 

Aging (Albany NY). 2016 Sep 14.

Targeting therapy for homocysteic acid in the blood represents a potential recovery treatment for cognition in Alzheimer's disease patients.
Hasegawa T1, Ukai W2.
...

 

 

I have also seen this. Am curious about the "open clinical trial that has shown impressive results".

[tunt01]

 

 

ceridwen is right: misfolded tau is the number one problem. And we need permanent immunity, not a new pharmaceutical drug addiction costing thousands of dollars per month.

 

The science is probably good, and the most important takeaway is that immune manipulation is a viable strategy with a lot of promise, absent something better like gene therapy.

 

If, in middle age, you can find this stuff on the black market and inject yourself sufficiently often to clear your amyloid, it just might help you. But that's easily 10 years down the road, by which time, tau vaccine will have completed stage 3 and China will probably be doing neural tissue grafts.

 

 

Phospho/misfolded tau is a downstream event from Abeta accumulation.  If the drug is removing Abeta and the MMSE scores are significantly better, the drug is presumably protective of tau.  If MMSE is still declining slightly on an absolute basis in the treated population, it may only indicate normal aging.

 

Again, I personally don't care for this kind of intervention, but it's compelling progress nonetheless.  If I had Alz, this would be pretty high up on the list.

[resveratrol_guy]

 

 

 

ceridwen is right: misfolded tau is the number one problem. And we need permanent immunity, not a new pharmaceutical drug addiction costing thousands of dollars per month.

 

The science is probably good, and the most important takeaway is that immune manipulation is a viable strategy with a lot of promise, absent something better like gene therapy.

 

If, in middle age, you can find this stuff on the black market and inject yourself sufficiently often to clear your amyloid, it just might help you. But that's easily 10 years down the road, by which time, tau vaccine will have completed stage 3 and China will probably be doing neural tissue grafts.

 

 

Phospho/misfolded tau is a downstream event from Abeta accumulation.  If the drug is removing Abeta and the MMSE scores are significantly better, the drug is presumably protective of tau.  If MMSE is still declining slightly on an absolute basis in the treated population, it may only indicate normal aging.

 

Again, I personally don't care for this kind of intervention, but it's compelling progress nonetheless.  If I had Alz, this would be pretty high up on the list.

 

 

I would think this should be high on the list for anyone with preclinical AD, such as mild cognitive impairment, traumatic brain injury, or double APoE4 status. Once one has contracted AD, the bang for the buck clearly isn't there, according to the earlier study. At that point, it would seem to make more sense to consume high-risk-high-reward substances which are also affordable, such as salsalate or perhaps mefenamic acid, in addition to obvious diet and lifestyle modifications, and perhaps mesenchymal stem cell therapy to shore up the BBB.

 

That said, I think your hypothesis may be correct that misfolded tau is downstream of misfolded amyloid. This would actually be consistent with the experimental results showing maximum benefit during the disease stage in which misfolded tau is a less significant consideration.

Edited by resveratrol_guy, 18 September 2016 - 06:35 AM.

[mag1]

TREGs and AD?

Might some Il-2 be therapeutic?

 

 

Immunotherapeutic effects of lymphocytes co-cultured with human cord blood-derived multipotent stem cells transplantation on APP/PS1 mice
https://www.ncbi.nlm...pubmed/27528555

Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer's disease model
https://www.ncbi.nlm...pubmed/27713140

 

 

[tunt01]

The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.

 

 

https://www.ncbi.nlm...pubmed/27567858

 

Assuming toxicity isn't an issue, this looks like a real cure for ALZ.

 

[mag1]

There has been recent discussion of moving CRISPR blood stem cell therapy forward for diseases such as sickle cell illness.

Would CRISPR modification of the APOE epsilon 4 allele in blood cell stem cells with subsequent transplant back into those

at risk for AD be helpful? 

 

 

http://hprd.org/summ..._name=Isoform_1

[resveratrol_guy]

There has been recent discussion of moving CRISPR blood stem cell therapy forward for diseases such as sickle cell illness.

Would CRISPR modification of the APOE epsilon 4 allele in blood cell stem cells with subsequent transplant back into those

at risk for AD be helpful? 

 

 

http://hprd.org/summ..._name=Isoform_1

 

The biggest problems is getting the CRISPR system through the BBB. In general, it's too large to do that, so there is current research into reducing its size by eliminating uncessary amino acids. The other method, craniotomy, is obviously highly undesirable from a risk standpoint, and also because the AAVs employed tend not to spread beyond a centimeter or so from the injection site. Frankly APoE4 would not be the only gene I'd want to toggle in AD, but it would be a start. It seems the first therapy along those lines will come from BioViva or one of their competitors.

 

@prophets: Interesting approach, although only a small minority of AD cases are due to APoE4. But perhaps the therapy would actually help heterozygous or noncarriers as well, depending on the precise mechanism of action of CS-6253. I wouldn't hold my breath, though.

 

[mag1]

res, sorry I was a bit obscure in my comments.

url below is talking of hematopoietic stem cells as a possible CURE for sickle cell disease with plans to move it to the clinic.

 

This would be just so amazing!

​They could lead off with some of the illnesses suggested and then scale up into others such as AD.

Having a well developed and established technology could create an assembly line of cures.

Pharmaceutical companies would have a path to the market and to a reasonable profit.

Trying to overplay their pricing power would simply result in a traffic jam of me toos. 

  

 

https://www.scienced...61012160205.htm

 

I was just going out a ways on the plank to suggest that CRISPRing blood cells to change the epsilon 4 genotype

might also be useful. In fact there are a range of possible blood stem cell interventions that could be of value in

AD ( for example, eotaxin-1, other factors in "young blood" [the Dracula cure]), among others. If anyone can add to the list, please do. Perhaps a protein that could degrade amyloid? The great part of all of this is that brain entry simply might be unnecessary. Lowering amyloid peripherally might draw the amyloid from the brain.  

 

If we are now beyond the BBB question the entire treatment horizon opens up. AD would no longer necessarily have to be thought of as disease of the brain at all, or at least the treatment could be directed elsewhere. For example, from what I remember the liver has substantial relevance to AD. I would be very interested to know whether one might

be able to CRISPR some liver stem cells perhaps the LXR gene and just inject away. Sort of like a genetic bexarotene.

 

https://www.ncbi.nlm...pubmed/17430243

 

In terms of the impact of APOE4 on AD, typically you are looking at 40-60% of AD being APOE epsilon 4. In fact, it often seems as though in many of the trials they like enriching for epsilon 4 because it can often be unclear whether many without epsilon 4 actually have true Alzheimer's.  

Edited by mag1, 20 October 2016 - 10:33 PM.

[tunt01]

 

 

@prophets: Interesting approach, although only a small minority of AD cases are due to APoE4. But perhaps the therapy would actually help heterozygous or noncarriers as well, depending on the precise mechanism of action of CS-6253. I wouldn't hold my breath, though.

 

 

Same mechanism as bexarotene.  Increases lipidation of HDL and improves cholesterol handling.  

[mag1]

Who's the red menace now?

Very scary picture of the global AD epidemic!

USA number 1?

 

Very scary picture of the global AD epidemic!

 

Does anyone know whether Portugal might accept refugees for those seeking sanctuary from

the global Alzheimer pandemic?

 

 

http://www.alzforum....andardized-rate

Edited by mag1, 22 October 2016 - 12:37 AM.

[resveratrol_guy]

Moving to Portugal won't help you, except maybe for the sardine industry over there. Although it looks blank white, it's actually in the middle of the scale. There are much better alternatives, although the statistics are skewed by competing causes of death that unfortunately win out early, as you can see in West Africa, for example.

 

I agree that CRISPR is the single most promising therapy for AD, but it's not in the clinic yet and frankly we shouldn't worry about it at this point, except to say that you might want to educate yourself about investment performance so you have the money if and when it arrives someday.

 

Maybe bexarotene is worth a second look.

 

For now, though, it's mostly about what (not) to eat.

[mag1]

I had had no idea that US was the universal centre of the AD pandemic.

 

And Finland?

Had no idea.

 

I would have thought that Japan would have been quite a bit higher on the list.

The confusing part is that this is not really concentrated on actual incident cases, so much on age specific rates. I am fairly confident that if you start changing the parameters around a different picture could emerge.

 

If you follow the links on my posted url then you can actually get to the GBD website and you can change things around.   

Edited by mag1, 22 October 2016 - 05:24 AM.

[corb]

Who's the red menace now?

Very scary picture of the global AD epidemic!

USA number 1?

 

Very scary picture of the global AD epidemic!

 

Does anyone know whether Portugal might accept refugees for those seeking sanctuary from

the global Alzheimer pandemic?

 

 

http://www.alzforum....andardized-rate

 

Looking at maps like these always makes me wonder if diet isn't only important in relation to a genotype or a very specific food item (in contrast to a whole food group) rather than in general. When it comes to meat and dairy consumption for instance the Balkans and Turkey are comparable, we live about as long on average and yet our AD rate is lower. We drink significantly more alcohol as well.

 

France and Greece eat twice the amount of cheese the US do. And yet - their rate of AD is again significantly lower. At the same time Finland eats a lot of cheese as well and they have a true  AD epidemic according to the statistics, not just this map - and yet it's not like Sweden has a different diet and their rates of both cancer and AD are measurably lower as far as I know.

 

Deviations like these really make me skeptical when it comes to diets. People are too fast to jump to conclusions.

 

[mag1]

BACE1 inhibitors for Alzheimer's!

Peer inside human genius and witness the ability of humanity to conquer any technological challenge.

 

The socio-cultural-technological trajectory of the 21st Century has now changed.

 

http://www.bionomics...omics_Merck.pdf

 

http://translational...0035-016-0061-5

[albedo]

http://www.longecity...nt/#entry794386

[mag1]

http://www.longecity...for-alzheimers/

[Avatar of Horus]

Some recent results about a new experimental drug NTRX-07, a potent and selective Cannabinoid receptor 2 agonist:

Therapy Seen to Restore Brain’s Ability to Clear Itself of Amyloid Plaques in Early Study
October 31, 2016    by Joana Fernandes, PhD
https://alzheimersne...d-plaque-clumps

Experimental drug shows promise in treating Alzheimer’s disease
10.25.16
https://www.asahq.or...heimers-disease

$1.7M Grant Given to Move Therapy Targeting Cannabinoid Receptor into Clinical Trials in Alzheimer’s Patients
September 28, 2016    by Charles Moore
https://alzheimersne...inical-testing/

 

[mag1]

Avator that was a good one.

Would love to see how BACE1 might combine with CB-2.

[Manwhoworkstoomuch!]

I recall reading on a new promising drug called aducanumab or something? Does anyone know anything about it?

[TRUGAN]

There was recently an article on nbc that talked about Psilocybin (magic mushrooms) were effective in treating depression and migraines which I have seen before but this time it briefly mentioned that Psilocybin may treat neurological conditions but it didnt say which ones. I briefly googled it and found something about it growing new neurons,

 

Anyone here familiar with this research and which neurological conditions it might treat and how it works? Is it telling the neurons to activate and clear out the garbage or just growing new ones?

[TRUGAN]

I still havent had much time to research Psilocybin but most of what I see suggests it grows neurons the way paxil does for depression so Im not sure if it does anything for other conditions or if it has even been looked at for such things yet.

It might be something to keep an eye on just in case but I dont really see the drug stores handing out Psilocybin pills any time soon unless they found a way to remove the hallucinating properties of it.

 

 

http://www.businessi...ections-2014-10

 

[ceridwen]

The side effects of Aducanumab are water on the brain and cysts in the brain. I don't think that would be worth it. There must be other ways...

[ceridwen]

As for the mushrooms I think the psychedelic side to them is the effect of the growth. They are good in the way that REM sleep is good a sort of waking dream.
The side effects of Aducanumab are water on the brain and cysts in the brain. I don't think that would be worth it. There must be other ways...

[mag1]

There has been quite a bit of excitement generated by a new generation of cancer vaccines.

 

Wonder whether a similar approach could be used in AD?  

 

 

http://biontech.de/2...herapy-vaccine/

http://biontech.de/

[TRUGAN]

As for the mushrooms I think the psychedelic side to them is the effect of the growth. They are good in the way that REM sleep is good a sort of waking dream.
The side effects of Aducanumab are water on the brain and cysts in the brain. I don't think that would be worth it. There must be other ways...

 

 

Maybe so. Maybe they will test it for more conditions eventually. I think a few hallucinations would be well worth the benefit if it can really repair a damaged brain.

[TRUGAN]

I dont know if ErgoD2 has been mentioned before but it might be worth taking for Parkinsons and Alzheimers.

 

I just found it late last night. 

 

 

http://www.totalnutr...in-d-supplement

 

https://www.michaelj...p?grant_id=1341

 

http://www.managedca...dical-food-show

 

http://www.biotechst...event-dementia/

 

https://globenewswir...ical-Model.html