1229 replies to this topic

[resveratrol_guy]

Longecity's internal search claims that the word bexarotene does not appear in this AD "goldmine" thread, which I find astounding. So sorry if this was already discussed synonymously, but I want to draw attention to this promising Alzheimer's treatment first mentioned by Elus. It started to look like a failure and subsequently lost public interest, but I think the criticism is overplayed if you read the details. Hopefully someone who knows a lot more than I do about this can run with it.

 

[GhostBuster]

Longecity's internal search claims that the word bexarotene does not appear in this AD "goldmine" thread, which I find astounding. So sorry if this was already discussed synonymously, but I want to draw attention to this promising Alzheimer's treatment first mentioned by Elus. It started to look like a failure and subsequently lost public interest, but I think the criticism is overplayed if you read the details. Hopefully someone who knows a lot more than I do about this can run with it.

 

So bexarotenes helps body to get rid of amyloid plaques. This has already been done with humans too. The problem is, that it seems that that has no clinical value, you don't cure alzheimer even if you remove the amyloid plaques. At least not in the late state alzheimer patients.

 

"Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration."

http://en.wikipedia....isease_research

 

 

http://en.wikipedia....rch#cite_note-3

Edited by GhostBuster, 02 December 2014 - 01:18 PM.

[tunt01]

Longecity's internal search claims that the word bexarotene does not appear in this AD "goldmine" thread, which I find astounding. So sorry if this was already discussed synonymously, but I want to draw attention to this promising Alzheimer's treatment first mentioned by Elus. It started to look like a failure and subsequently lost public interest, but I think the criticism is overplayed if you read the details. Hopefully someone who knows a lot more than I do about this can run with it.

 

It's been discussed a bit.  I can't find the thread, but I suggest you search for them.  There are some issues I would point out:

 

- Dosage.  The dose used in the rat (or was it mice?) studies implied an enormous dose in humans.  I can't recall off the top of my head, but the Human Equivalent Dosage (HED) for bexarotene in treating Alzheimers was nothing like the dose levels used in its original intended medical condition (cancer treatment).  Such that, I think one has to be very careful from a toxicity perspective in taking some super dose of Bexarotene.  I've not looked into it carefully, but I would tread lightly.  I only looked briefly, so I did not take notes.  But I remember the Alzheimers doage being something like 5-10x or more than the cancer indicated dosage levels.

 

- Side effects.  Unreleased data in one of the mice papers said that triglyceride production was abnormally high.  Bexaortene seems to have an effect on the liver which triggers very significant triglyceride production.  IDK how bad or serious this is, because they didn't disclose the data.  But I'd personally wait to see human trials.

 

- The mechanism by which Bexarotene "prevents" alzheimers is through ABCA1 cholesterol transporter, which is found throughout the body.  It mediates cholesterol efflux in key brain cells (astrocytes, glial).  Bexarotene improves this cholesterol handling, which is a deficiency in those with alzheimers.  Also, individuals with APOE4 genes tend to have lower HDL cholesterol levels and ABCA1 is implicated in the biogenesis of HDL.  (Side Note:  I would personally guess almost anything that improves HDL in an APOE4 carrier, would probably have preventative effects re: ALZ)

 

Hence the issue is ABCA1 and what is termed as its lipidation capability.  Based on some cursory reading, I think telmisartan, curcumin are more safe/appropriate choices for improving ABCA1 functionality.  There are certainly trade-offs in any choice.  If I recall, the relative risk is about 20% higher for lung cancer in some telmisartan studies.

 

Anyhow, I would just throw out that flag of caution on bexarotene until we know more and suggest one consider Telmisartan/Curcumin, which seem to operate through the same ABCA1 pathway.

Edited by prophets, 02 December 2014 - 11:38 PM.

[resveratrol_guy]

"Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration."

http://en.wikipedia....isease_research

 

 

http://en.wikipedia....rch#cite_note-3

 

 

That quote is not found at either of those links. Please provide a working link if you can find it again. I've often remarked that amyloid plaque might be the "gray hair" of Alzheimer's, as opposed to the root pathology, so I'm interested in any evidence for or against this hypothesis.

 

@ prophets: Good info, sorry to hear that. Yeah sounds like this substance is DOA for those reasons.

[GhostBuster]

 

"Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration."

http://en.wikipedia....isease_research

 

 

http://en.wikipedia....rch#cite_note-3

 

 

That quote is not found at either of those links. Please provide a working link if you can find it again. I've often remarked that amyloid plaque might be the "gray hair" of Alzheimer's, as opposed to the root pathology, so I'm interested in any evidence for or against this hypothesis.

 

@ prophets: Good info, sorry to hear that. Yeah sounds like this substance is DOA for those reasons.

 

For some reason, the link seems to go the wrong page even though the address should be right.

 

Ok, here's the link again:

 

http://en.wikipedia....isease_research

 

If it still goes to the alzheimer wikipedia main page, then google alzheimer's disease research + wikipedia, and you´ll find the right page.

 

Here's the context of quote:

 

Immunotherapy to amyloid beta

Immunotherapy or vaccination for Alzheimer's stimulates the immune system to attack beta-amyloid. One approach is active immunization, which would stimulate a permanent immune response.^[2] The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.^[3]

[resveratrol_guy]

For some reason, the link seems to go the wrong page even though the address should be right.

 

Ok, here's the link again:

 

[2] The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.

 

^{Got it, finally. Here is the latest re-re-re-reassessment of this study, in the Lancet with a link that I tested after posting this. It actually sounds worse than you said, in the sense that "Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival".}

 

^{So if I combine this with what you quoted above, it sounds like: Amyloid is smoke, not fire. If you blow the smoke out of a burning building, then people inside it be able to function better in the short term, but the building will still collapse on them in essentially the same time period. Pragmatically, this means we should clear amyloid using only cheap and low-risk strategies, e.g. Longvida, EGCG, maybe turmeric; but we should redirect all amyloid research resources to tauopathy. Now we're back to ADNP, NAP (davunetide), and desparate stuff like insulin nasal spray. That's no fun because they only work in isolated regimes, it seems. If I had to bet my life on it (and I suppose we all are, to some extent), I'd put my money on LLLT/TULIP (thanks, lostfalco), nicotinamide riboside, and/or c60oo. I'd also make one very easy bet: we'll see the best tauopathy therapies on Longecity years before they appear at the doctor's office, if they ever do.}

 

^{As disappointing as this is, you deserve credit for digging up the data. I'm surprised, frankly, that this doesn't seem to be more widely known, even in neurological circles. Maybe the vaccine will work well for certain narrow populations, but I think it's time to attack tauopathy head-on. Artificial neurons, anyone?}

 

^{@ Mods: We seem to have problems with URLs containing "#" or "_", as above. Not sure.}

Edited by resveratrol_guy, 04 December 2014 - 11:41 PM.

[mag1]

Our family is currently coping with severe Alzheimer's disease and a family history is present.

Even though the AN 1792 study was a disappointment, it should be noted that the second second generation
amyloid vaccine solanezumab (bapineuzumab {the followup to AN1792 was the first second generation vaccine}) reported statistically significant results in pre-specified endpoints in phase 3 trials and is currently conducting additional phase 3 trials for a possible FDA filing in early stage AD. Solanezumab appears to slow AD progression in those with mild dementia by 30-40%. Giving this vaccine even earlier would likely be even more helpful. So on the MMSE when they ask you for the serial sevens the smart choice would be 92 to start.

Methylene blue is also of interest. This first generation tau treatment has fully enrolled 2 phase 3 trials in Alzheimer's which should finish within a year. We could then have a much better sense of the importance of tau relative to amyloid in AD.

At the same time, it should be noted that the discovery of a SNP (rs63750847-A) in the APP gene that reduces amyloid levels by 30-40% and cognitive impairment in advanced ages has generated considerable interest in the research community. This discovery added a completeness to the logic of the amyloid perspective: High amyloid (e.g. from causative AD genes (PSEN1, PSEN2, APP)) causes dementia, yet low amyloid (e.g. APP's rs63750847-A) decreases risk of AD. Current drugs in late stage development have the ability to reduce amyloid levels by over 90%. Consider the implications for reducing the risk of dementia if such drugs were used throughout life preventatively.

A recent study has also suggested that AD might already be reversible. This study found that a multi-prong treatment
was able to reverse early dementia symptoms. This study noted that current pharmaceutical approaches are trying to address the complex pathology of dementia using a single drug approach. They advocate for a drug cocktail strategy (similar to HIV treatment).

(See note at top of page in yellow).
http://www.apoe4.inf...d=active_topics

[resveratrol_guy]

Methylene blue is also of interest. This first generation tau treatment has fully enrolled 2 phase 3 trials in Alzheimer's which should finish within a year. We could then have a much better sense of the importance of tau relative to amyloid in AD.

 

This is all I could find with relevance to the brain. Got any links to those trials?

 

http://clinicaltrial...how/NCT01836094

http://clinicaltrial...how/NCT00214877

 

The other vaccine you mentioned is interesting. I wonder if it works, not by reducing amyloid, but by fixing some other underlying problem which happens to result in better amyloid clearance.

 

[mag1]

Sorry, I was not clear about methylene blue. 

 

TauRx, the company behind the phase 3 studies, has reformulated methylene blue (possibly for patent concerns but also for better absorption etc)

into a substance called LMTX. Two phase 3 clinical trials in AD have fully enrolled and should report in about a year. There is another phase 3 trial for fronto-temporal dementia.

 

The phase 2 placebo controlled randomized trial in mild to moderate AD for methylene blue reported almost complete stabilization in the treatment arm. However, there are some questions about this trial. It would be wonderful if the phase 3 trials confirm the initial results. It is unclear why this is the first tau trial in AD given the thought leaders in AD research have known for many years that tau is likely the driver of the neurodegeneration.

 

The Solanezumab and Bapineuzumab phase 3 trials were also difficult to explain. Why did these pharmaceuticals invest billions of dollars investigating these anti-bodies in later stage AD when the AN1792 study found no benefit to clearing amyloid in the later stages. Companies that can bring an amyloid lowering medication will make an enormous amount of money. It will be like a statin for the brain. Marketing pharmaceuticals to mostly the worried well, many of whom might never develop clinical dementia, is a recipe for success. 

 

 

The results of the AD04 phase 2 trial from AFFiRiS should also be noted. AFFiRiS reported very positive results for AD04 and has stated their intention to move the product forward. Amusingly, when reading through the recent glowing press release there is no mention that AD04 was actually the placebo!

 

http://www.affiris.c...seII_E_0603.pdf

 

It is very Orwellian.  However, if this can cure or offer an effective treatment for AD, then all the power to them. 

[GhostBuster]

 

For some reason, the link seems to go the wrong page even though the address should be right.

 

Ok, here's the link again:

 

[2] The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.

 

^{Got it, finally. Here is the latest re-re-re-reassessment of this study, in the Lancet with a link that I tested after posting this. It actually sounds worse than you said, in the sense that "Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival".}

 

I find it surprising that the herpes simplex theory of Alzheimer doesnt bring more attention. It is after all very elegant, heuristic and simple theory. And not that extraordinary or out of the box theory. It also seems that it has gain more popularity lately among researchers. I think that in the following paper the dots are connected  pretty impressively, there's a lot more to read than just an abstract.

 

Alzheimer's disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction.

 

http://www.ncbi.nlm....pubmed/21167244

 

These are some of my personal favorites (among already bolded citations in the earlier post)

"The ubiquitin–proteasome system, necessary for the elimination of abnormal proteins such as beta-amyloid and tau, is dysfunctional in Alzheimer's disease ( Paul, 2008), a situation that might well be induced by the effects of the virus on the chaperone/proteasome/ubiquitin machinery."

 

"Paradoxically, while the immune system is suppressed, the virus and the host cells could peacefully coexist, while immune activation and viral destruction might be at the terrible cost of neuronal death."

 

"During its sojourn in the brain, the virus exists predominantly in a latent state, where few viral proteins are expressed. Indeed, during this state the virus may exert protective effects via inhibition of apoptosis and the promotion of neurite growth (Li et al., 2010). However, reactivation from time to time may occur, that could reignite the host/pathogen battle."

 

"There are, for example, multiple actins, ADP ribosylation factors, annexins, heterogeneous ribonucleoproteins, integrins, RABs, heat shock or 14-3-3 proteins, but those found in plaques or tangles are precisely the ones that bind to the virus."

 

 

 

 

 

 

 

[mag1]

http://news.investor...s-drug-news.htm

[corb]

 

An oldy but a goody. Published 1976.

http://www.jimmunol..../1/156.abstract

 

Thymosin Restores T Cell Function and Reduces the Incidence of Amyloid Disease in Casein-Treated Mice¹

1. Morton A. Scheinberg,
2. Allan L. Goldstein and
3. Edgar S. Cathcart²

+ Author Affiliations

1. From the Arthritis and Connective Tissue Disease Section, Evans Department of Clinical Research, University Hospital and the Thorndike Memorial Laboratory and Division of Medicine, Boston City Hospital, Boston, Massachusetts 02118 and from the Division of Biochemistry, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas

Abstract

Evidence is presented that T cell impairment appears to be specifically related to the pathogenesis of experimental amyloidosis. This conclusion is based on the finding that thymosin administration improves T cell function as measured by mitogen stimulation of spleen cell suspension and at the same time reduces the incidence and severity of amyloid disease in casein-treated mice.

 

Based on the Alzheimer's vaccines to activate T cells often reducing local proinflammatory markers one would wonder if T cell impairment was more causative than correlative in AD. If that proved to be true TB4 could slow the progression of the disease,....Based on forgotten data from 1976.

 

 

Wait a fricking minute!

 

 

in Casein-Treated Mice¹

Are they inducing AD with casein? That stuff is quite abundant in dairy products.

Is it unsafe for the old to consummate dairy products? Most pensioners in my parts of the world live on yogurt, cheese and bread - it's the staple of their diet anyway.

 

I'd really like to know this.

[aribadabar]

Casein is not good for anyone, old or young adults. It is a pro-inflammatory protein which causes an elevated systemic inflammation with nothing good to show for this.

Some bodybuilders take it for "growth" via IGF-1 pathway at their own peril...whey is the least of all evils when it comes to dairy proteins.

[niner]

How did the mice get the casein?  Orally or injected?  That's an important difference.

[mag1]

Update on AFFiRiS  AD04, that is the placebo from a recent study. It turns out that the placebo that was used is alum. This is very strange, as there is a body of evidence that suggests that aluminum causes Alzheimer's disease. The 2 mg alum dosage arm performed better than expected. It is of note, though, that  

a 2 mg alum dose exceeds the FDA's safety limit, yet not the European's.

[forever freedom]

Has anyone seen this or posted it here?
This Stanford team seems to be into something big, possibly even curing Alzheimers soon:

http://med.stanford....alzheimers.html

Edited by forever freedom, 06 January 2015 - 09:48 AM.

[ta5]

Sci Rep. 2015 Jan 23;5:7992.

Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity.

Du WJ1, Guo JJ1, Gao MT1, Hu SQ2, Dong XY3, Han YF2, Liu FF3, Jiang S4, Sun Y3.

Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 ± 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

PMID: 25613018

[niner]

Here's the structure of brazilin.  It looks like it would have resveratrol-ish PK. 

 

 Capture.GIF   8.82KB   3 downloads

Edited by niner, 28 January 2015 - 04:40 AM.

[Logic]

"The mass die-off of nerve cells in the brains of people with Alzheimer’s disease may largely occur because an entirely different class of brain cells, called microglia, begin to fall down on the job, according to a new study by researchers at the Stanford University School of Medicine...

...The Stanford study provides strong evidence that this deterioration in microglial function is driven, in large part, by the heightened signaling activity of a single molecule that sits on the surface of microglial and nerve cells. Previous work in Andreasson’s lab and other labs has shown that this molecule, a receptor protein called EP2, has a strong potential to cause inflammation when activated by binding to a substance called prostaglandin E2, or PGE2..."

http://med.stanford....alzheimers.html

EP2 Antibodies
http://www.scbt.com/table-ep2.html

Edited by Logic, 28 January 2015 - 10:00 PM.

[ta5]

J Alzheimers Dis. 2015 Jan 29. 

Observational and Ecological Studies of Dietary Advanced Glycation End Products in National Diets and Alzheimer's Disease Incidence and Prevalence.

Perrone L1, Grant WB2.

Background: Considerable evidence indicates that diet is an important risk-modifying factor for Alzheimer's disease (AD). Evidence is also mounting that dietary advanced glycation end products (AGEs) are important risk factors for AD. Objective: This study strives to determine whether estimated dietary AGEs estimated from national diets and epidemiological studies are associated with increased AD incidence. Methods: We estimated values of dietary AGEs using values in a published paper. We estimated intake of dietary AGEs from the Washington Heights-Inwood Community Aging Project (WHICAP) 1992 and 1999 cohort studies, which investigated how the Mediterranean diet (MeDi) affected AD incidence. Further, AD prevalence data came from three ecological studies and included data from 11 countries for 1977-1993, seven developing countries for 1995-2005, and Japan for 1985-2008. The analysis used dietary AGE values from 20 years before the AD prevalence data. Results: Meat was always the food with the largest amount of AGEs. Other foods with significant AGEs included fish, cheese, vegetables, and vegetable oil. High MeDi adherence results in lower meat and dairy intake, which possess high AGE content. By using two different models to extrapolate dietary AGE intake in the WHICAP 1992 and 1999 cohort studies, we showed that reduced dietary AGE significantly correlates with reduced AD incidence. For the ecological studies, estimates of dietary AGEs in the national diets corresponded well with AD prevalence data even though the cooking methods were not well known. Conclusion: Dietary AGEs appear to be important risk factors for AD.

PMID: 25633677

[Turnbuckle]

 

... we showed that reduced dietary AGE significantly correlates with reduced AD incidence. For the ecological studies, estimates of dietary AGEs in the national diets corresponded well with AD prevalence data even though the cooking methods were not well known. Conclusion: Dietary AGEs appear to be important risk factors for AD.

PMID: 25633677

 

 

If that is the case, then diabetes should be associated with Alzheimer's, as the resultant high blood sugar produces more AGEs--

 

Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain.

 

http://www.ncbi.nlm....les/PMC2769828/

 

 

And thus supplements that normalize the body's ability to use insulin should be protective. Like cinnamon--

 

The strong connection between Alzheimer’s and diabetes is no secret. With almost 70% of people with type II diabetes ultimately developing Alzheimer’s, some researchers believe Alzheimer’s may be a type of diabetes. It is interesting to note that cinnamon has been shown to have positive effects on those with type II diabetes by lowering their blood sugar. One recent study found that participants who had diabetes lowered their blood sugar by up to 29% by consuming 1/4 teaspoon of cinnamon twice a day for 40 days.

 

http://www.alzheimer...nts-alzheimers/

 

[mag1]

Could someone help out here?

Minicells have shown a profound ability to treat cancer. Dosing with 520 nanograms of chemotherapy in minicells was found to
have a curative effect in mice with cancer. [See page 5 figure 1A from http://www.tandfonline.com/doi/pdf/10.4161/cc.6.17.4648 ]


A human phase 1 cancer trial has been reported.

Minicells specifically target cancer cells with particular cell surface receptors.

Might minicells also help in Alzheimer's? What specific receptors could be targeted? For Alzheimer's, liver cells which make APOE or immune cells could be possible targets. Minicells loaded with miRNA, etc. might have a therapeutic effect.

Any comments?

[ceridwen]

The insulin deficiency in the brain does not show in the blood possibly because of the blood brain barrier. I am currently taking Niagen. There is also artunat clinical trial going on. Niagen 1500mg a day for 24 weeks.I seem to be getting good results with this. I've been on it 3 days so far and this is the only thing that works for me. Unfortunately it is milk based. Does anyone know is there an equivalent whose filler does not appear to be powdered milk? I am considering cycling it and on the days I don't take it cutting out carbs and sugar and doing the regium that has been proved to work for mild Alzheimer's patients. I am also developing a some theories of my own to do with dysfunctional MTHF? pathway. There's a possibility that it is not only a form of diabetes but MTHF is also not working. It could be a very severe form of pyoluria too. Diabetes may be too? Pyoluria could be at the base of all chronic disease. GPS are very reluctant to treat chronic disease properly with their 5 minutes suits all policy and the cure might be supplements zinc,B6 and finding a Dr who will take the time to do the proper tests a recommendations. Niacin helps overmethylators. B6 and Zinc under methylators if I understand correctly. It really takes a good Dr to sort it all out a luxury I don't have. At the moment I want to explore all and any solutions and the mini cells sound interesting too I'd like to know more about them. I have a feeling that Niagen might be a useful treatment and that a moulti pronged approach is the right way to go.

[ceridwen]

Mini cells early on perhaps even for mild memory loss because I'm sure that when things start to go wrong it happens on a microscopic level as the scans come back looking almost normal and unless you look at a microscopic level people can't be helped. Unfortunately at present there are few scanners that could tackle the resolution.
So mini cells used then could be particularly useful.

[ceridwen]

Is there anything left that one can eat if one wants to avoid AGEs?

[niner]

Is there anything left that one can eat if one wants to avoid AGEs?

 

Dietary AGEs are mostly formed by high temperature cooking methods.  Helen Vlassara has published a low-AGE cookbook that helps you get dietary AGEs under control without much impact on your diet.  There are certain things that you want to avoid, but a lot of normal foods that aren't too bad.  Raw fruits and vegetables should be golden.  Foods cooked in water or steam would be better than the same thing that was fried or baked.

[niner]

The insulin deficiency in the brain does not show in the blood possibly because of the blood brain barrier. I am currently taking Niagen. There is also artunat clinical trial going on. Niagen 1500mg a day for 24 weeks.I seem to be getting good results with this. I've been on it 3 days so far and this is the only thing that works for me. Unfortunately it is milk based. Does anyone know is there an equivalent whose filler does not appear to be powdered milk? I am considering cycling it and on the days I don't take it cutting out carbs and sugar and doing the regium that has been proved to work for mild Alzheimer's patients. I am also developing a some theories of my own to do with dysfunctional MTHF? pathway. There's a possibility that it is not only a form of diabetes but MTHF is also not working. It could be a very severe form of pyoluria too. Diabetes may be too? Pyoluria could be at the base of all chronic disease. GPS are very reluctant to treat chronic disease properly with their 5 minutes suits all policy and the cure might be supplements zinc,B6 and finding a Dr who will take the time to do the proper tests a recommendations. Niacin helps overmethylators. B6 and Zinc under methylators if I understand correctly. It really takes a good Dr to sort it all out a luxury I don't have. At the moment I want to explore all and any solutions and the mini cells sound interesting too I'd like to know more about them. I have a feeling that Niagen might be a useful treatment and that a moulti pronged approach is the right way to go.

 

The NR must be helping.  You sound better here than you have in the past.  Commercial NR isn't milk based.  It's expressed in a microbial culture of some sort or another; possibly yeast.  The capsule doesn't use powdered milk as a filler.  Whatever the filler is, if there's one at all, is most likely listed on the bottle.

[Turnbuckle]

 

Is there anything left that one can eat if one wants to avoid AGEs?

 

Dietary AGEs are mostly formed by high temperature cooking methods.  Helen Vlassara has published a low-AGE cookbook that helps you get dietary AGEs under control without much impact on your diet.  There are certain things that you want to avoid, but a lot of normal foods that aren't too bad.  Raw fruits and vegetables should be golden.  Foods cooked in water or steam would be better than the same thing that was fried or baked.

 

 

 

Wouldn't dietary AGEs be broken up during digestion? And wouldn't they be intrinsically different from endogenous AGEs, as they wouldn't be crosslinking cellular proteins?

[Turnbuckle]

To answer my own question, especially in the case of diabetes--

 

Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy

 

The increases in AGE concentration in serum and urine of normal individuals after ingesting the AGE-rich protein meal confirmed that AGE moieties present in foods survive the digestive process and are transported, as small molecular weight particles into the bloodstream, along with short peptides and amino acids present in the digest, in a manner directly proportional to the amount ingested. Although not more than 10% of ingested AGEs was accounted for in the intravascular space, an additional portion is likely to be distributed to the extravascular space along with endogenously formed AGEs. Consistent with previous reports, however, (mt)70% of the ingested advanced glycation products escape absorption, probably due to the documented resistance of AGE crosslinks to enzymatic or acid hydrolysis in the digestive tract (11, 13).

 

Only one-third of the absorbed AGEs appearing in the serum was detected over the ensuing 48 hr in the urine, the fate of the other two-thirds remaining undetermined (11, 13). Although a portion of that could conceivably be excreted slowly, at a rate below baseline over the ensuing days or weeks, a valid explanation is that it is incorporated covalently onto tissues and cells. The enhanced capacity of diet-derived serum AGEs to form complexes with a native protein (e.g., fibronectin) shown here supports this notion and suggests that the daily ingested glycotoxins are retained in various tissues over time. The effective inhibition of the chemical reactivity of diet-derived serum glycotoxins by aminoguanidine further supports their potentially toxic nature. This is also supported by earlier studies of rats fed AGE-modified diets for up to 12 months that showed kidney (and liver) enlargement and cumulative pigment deposition in these organs, or by the chronic infusion of animals with AGEs resulting in accelerated, diabetes-like vascular, and renal lesions (24–26). In addition to targeting matrix components (8), glycotoxins can attach onto the LDL particle (9), resulting in slower clearance and higher plasma LDL concentration, a well known atherogenic condition (9, 19). It can be anticipated that, in humans as well, the steady influx of food-derived AGEs serves as a permanent source of glycotoxins, a part of which is added daily onto the total body burden. Thus, the amount of food-derived AGEs ingested daily over many decades can be regarded as clinically significant, given the striking rise in serum AGE (after a single test) to levels even higher than the level of diabetic renal failure.

 

 

 

 

[corb]

 

^{So if I combine this with what you quoted above, it sounds like: Amyloid is smoke, not fire. If you blow the smoke out of a burning building, then people inside it be able to function better in the short term, but the building will still collapse on them in essentially the same time period. Pragmatically, this means we should clear amyloid using only cheap and low-risk strategies, e.g. Longvida, EGCG, maybe turmeric; but we should redirect all amyloid research resources to tauopathy. Now we're back to ADNP, NAP (davunetide), and desparate stuff like insulin nasal spray. That's no fun because they only work in isolated regimes, it seems. If I had to bet my life on it (and I suppose we all are, to some extent), I'd put my money on LLLT/TULIP (thanks, lostfalco), nicotinamide riboside, and/or c60oo. I'd also make one very easy bet: we'll see the best tauopathy therapies on Longecity years before they appear at the doctor's office, if they ever do.}

 

^{As disappointing as this is, you deserve credit for digging up the data. I'm surprised, frankly, that this doesn't seem to be more widely known, even in neurological circles. Maybe the vaccine will work well for certain narrow populations, but I think it's time to attack tauopathy head-on. Artificial neurons, anyone?}

 

^{@ Mods: We seem to have problems with URLs containing "#" or "_", as above. Not sure.}

 

 

It's even worse than you think. I've noticed a couple of articles from the recent one or two years calling for Alzheimer's to be researched as a syndrome and not a disease - in other words, they're admitting it's too complex and an exact cause cannot be identified at the moment - they're throwing the towel.

 

But that's not all bad because they'll finally concentrate on alternative treatments that have shown good results, they might look at new drug targets, like - clogged mitochondria, dysfunctional ribosomes - the articles posted here about the limiting of AGEs and Alzheimer's being viewed as a new type of diabetes are a good direction for the very short term, prevention might actually be more effective than any treatment we have right now.

 

You're skeptical about NAP, but I've read that NAP, humanin and colivelin for instance have shown some very good results at protecting the neurons.