1229 replies to this topic

[mag1]

​Thanks, for the advice about not overdoing gamma entrainment, prophets.

Sometimes I can get carried away with things.

 

Wonder what would happen to the mice if they were treated for 12 hours a day for a week?  

 

Hmm, from the Nature commentary on the gamma research:

 

"Moreover, disruption of gamma oscillations has been observed in several neurological conditions, including brain trauma, schizophrenia and Alzheimer's disease^2""

 

Also, from the Nature article:

​"These results reveal deficits in gamma modulation of CA1 spiking in a mouse model of AD before the development of major amyloid plaque accumulation or evidence of cognitive impairment. This deficit in gamma converges with evidence of gamma deficits in different mouse models of AD, and reports that gamma is altered in humans with AD^{5, 8, 9   "}

 

People who are worried about AD could have their gamma checked.

 

​"The fact that GABA_A antagonist treatment completely abrogated the effects of 40 Hz stimulation on Aβ levels strongly suggests that GABAergic neurotransmission is critical for these effects"

 

Cognitive testing appears not to have been done for confirmation.

Is the connection between amyloid and cognition in mice so well established that it is felt unnecessary?

 

The article speaks only of amyloid reduction occurring in the visual cortex (not hippocampus) after flicker therapy.

Would this help in AD prevention?

 

Would be very interested to see the result of combo BACE inhibitor and gamma.

Perhaps this might be a way for this to enter clinical medicine.      

  

 

 

Edited by mag1, 08 December 2016 - 08:09 PM.

[mag1]

On the right hand column beside the Nature article there is an accompaning audio in which further commentary is added.

Of course, they used the line about these being disco mice with their strobe lights. And they suggested that the young

people going out clubbing will be preventing Alzheimer's.

 

It was interesting that they also mentioned that a wider range of neurological illness than were mentioned in the article

might now be considered for this line of therapy including Parkinson's and autism.

 

Also it was very interesting to hear that the researchers intend to move this research into AD patients in the next few months!

Very good news. 

[tunt01]

The article speaks only of amyloid reduction occurring in the visual cortex (not hippocampus) after flicker therapy.

Would this help in AD prevention?

 

Would be very interested to see the result of combo BACE inhibitor and gamma.

Perhaps this might be a way for this to enter clinical medicine.      

 

Unless the intervention changed gamma waves in a broad network of neurons across multiple parts of the brain, I think it would be a very minor benefit in the visual cortex alone.  It's hard to know without having seen the paper.

 

Ground zero for alzheimer is probably the locus coeruleus and the damage spreads outwards toward the hippocampus, etc.  Visual cortex is not the epicenter of the damage/neurodegeneration/amyloid generation.

 

BACE1 inhibitors are an important class of drug therapies.  They obviously changes how APP is processed and how much amyloid is outputted.

 

I personally think the 'holy grail' will be drugs that affect amyloid beta clearance mechanisms around increased Neprilysin, Insulin Degrading Enzyme (IDE), Hsp70 and LRP1/2.  These mechanisms are most affected by exercise, which I think is the best intervention.  If exercise is the best way to prevent alzheimer's, then its effect should be the blueprint for the best anti-alzheimer intervention.

 

I think the essence of having durable, long lifespan is dealing with damage after it occurs (not just with alzheimer).  It's an issue of proteostasis.  I think it isn't that we want to prevent amyloid beta generation, it is that we need to deal with its aggregation, misfolding and clearance.  That's why increasing natural clearance mechanisms I think are more important than preventing its generation in the first place, assuming one doesn't already suffer from an inflammatory disorder.

[mag1]

If amyloid reduction is very specific to only localized regions of the brain based on mode of stimulation then perhaps multimodal would be the way to go.

 

visual entrainment for the visual cortex,

audio entrainment for the audio cortex,

and tactile ... perhaps others.

 

Wonder also about using this as electromagnetic stimulation.

 

The researchers must think this is promising if they intend to start up a clinical trial in AD in the next few months.     

[mag1]

https://www.transpar...p.com/research/

[mag1]

Perhaps it would be best to look at those subgroups of AD patients which might espcially benefit from gamma in the initial clinical trials. 

 

https://www.ncbi.nlm...pubmed/27335037

[Heisok]

Dr. Tsai at the end of an interview about their work indicates that she has lighted her christmas tree with colored LED lights at Gamma of 40 Hz .

 

Looks like Radiolab signed a non-disclosure in order to get early access to the research. It is an excellent interview for a non scientist such as myself who might also be slightly impaired. Along with Dr. Tsai et al's work, they discuss the work of another lab who has experimented using mice to recover fear memories. It involved electro stimulating mice in a certain environment. Establishing that the mice reacted later with fear. Then later still, that the mice had completely forgotten that that environment was something to be afraid of. They implanted and then stimulated a part of the brain. The mice recovered the memory that they should be afraid of that environment.

 

Towards the end of the interview, the interviewers mentioned that they are going to try to quickly move to human studies of some sort.

 

http://www.radiolab....ing-gamma-back/

 

Gamma frequencies were discussed extensively in a Longecity thread a while back. Anecdotal evidence of cognitive benefits for some.

 

 

http://www.longecity...mazing-results/

 

Edited by Heisok, 08 December 2016 - 11:20 PM.

[mag1]

Is LED lighting actually relevant to the effect that was found in the Nature article?

Is it not more related to simply gamma entrainment? 

[Heisok]

Listen to about 12 minutes in. They created a "flicker" room where the hole in the head was essentially the eyes. The flicker was from strips of led lights that flicker at 40 on off cycles per second if I heard correctly! 50% reduction only from bulbs at 1 hour. Also a 7 day study with more impaired mice also resulted in a 50 % reduction.. But the treatment is not persistent. They have to complete a treatment every 24 hours or so.

Edited by Heisok, 09 December 2016 - 12:58 AM.

[mag1]

Anyone have access to the presentation from CTAD for the LMTX phase 3?

taurx's press report seems to be cautiously avoiding calling the phase 3 a success.  

 

http://taurx.com/upl...nical-Trial.pdf

Edited by mag1, 09 December 2016 - 03:19 PM.

[mag1]

Yeah, about doing 12 hours per day of gamma, well I tried that for one day and that was about all I could take of it.

It seemed like getting a bit too wired up on a few extra coffees in the morning.

 

Anyone else notice that effect?

 

With beta entrainment, well sure, I have that on all the time and it can just fade into the background.

Gamma was a bit too energizing.

 

 

[tunt01]

Add CTB-MBP to the list of interventions to keep an eye on.  It'd be pretty hard to swing a group buy on this product, but maybe some enterprising chemist/botanist could delve into the manufacturing process and somehow come with it.  I highly doubt it though.

 

 

Oral delivery of bioencapsulated proteins across blood-brain and blood-retinal barriers.

Kohli, et al.  Mar. 2014.

 

Delivering neurotherapeutics to target brain-associated diseases is a major challenge. Therefore, we investigated oral delivery of green fluorescence protein (GFP) or myelin basic protein (MBP) fused with the transmucosal carrier cholera toxin B subunit (CTB), expressed in chloroplasts (bioencapsulated within plant cells) to the brain and retinae of triple transgenic Alzheimer's disease (3×TgAD) mice, across the blood-brain barriers (BBB) and blood-retinal barriers (BRB). Human neuroblastoma cells internalized GFP when incubated with CTB-GFP but not with GFP alone. Oral delivery of CTB-MBP in healthy and 3×TgAD mice shows increased MBP levels in different regions of the brain, crossing intact BBB. Thioflavin S-stained amyloid plaque intensity was reduced up to 60% by CTB-MBP incubation with human AD and 3×TgAD mice brain sections ex vivo. Amyloid loads were reduced in vivo by 70% in hippocampus and cortex brain regions of 3×TgAD mice fed with bioencapsulated CTB-MBP, along with reduction in the ratio of insoluble amyloid β 42 (Aβ42) to soluble fractions. CTB-MBP oral delivery reduced Aβ42 accumulation in retinae and prevented loss of retinal ganglion cells in 3×TgAD mice. Lyophilization of leaves increased CTB-MBP concentration by 17-fold and stabilized it during long-term storage in capsules, facilitating low-cost oral delivery of therapeutic proteins across the BBB and BRB.

 

 

 

 

 

 

 

CTP-MBP is a combination cholera toxin B subunit (CTB) married to myelin basic protein (MBP).  The CTB fragment allows the entire molecule to pass through the blood brain barrier (BBB) and the MBP is active in clearing amyloid beta.  The molecule is (at least partly) created in a specially grown tobacco leaf, with genetically engineered chloroplasts that express the cholera component.

 

 

3xTgAD Mice treated with CTB-MBP showed a ~70% reduce in AB42 levels.

 

Quantitative evaluation of amyloid levels in triple transgenic Alzheimer's disease (3×TgAD) mice on CTB-MBP oral delivery. 

 

(d). *P < 0.05. AD, Alzheimer's disease; CTB, cholera toxin B subunit; MBP, myelin basic protein; WT, wild type.

 

 

 

In vivo evaluation of amyloid plaque load on orally delivered CTB-MBP in triple transgenic Alzheimer's disease (3×TgAD) mice. (a,b) Representative images of the cortical and hippocampal brain sections of 12- to 14-month old 3×TgAD mice fed with either recombinant CTB-MBP bioencapsulated in plant cells (31.2 µg/300 µl/day; n = 8 mice), wild type (WT) leaf extracts (300 µl/day; n = 4 mice), or unfed (n = 4 mice). Sections were stained for amyloid plaques with either anti-Aβ antibody 2454 (red fluorescence; a) or thioflavin S (ThS) (green fluorescence; b) and with DAPI ((4′,6 diamidino-2-phenylindole) blue) to label cell nuclei. Bar = (i) hippocampus 100 µm and (ii) 10µm at different magnifications and (iii) cortex 10 µm). (c) Quantification of the relative amounts of amyloid plaque load in the anti-Aβ and ThS-stained sections from the animals fed with CTB-MBP or WT protein extracts as described in (a,b). The mean plaque counts in the DG, CA1, and CA3 hippocampal and mantle and pallium cortical regions per section were determined with NIS Elements for Advanced Research. The values in the histogram represent the mean ± SD> n= 63; single factor analysis of variance *P < 0.05 for cortex, **P < 0.01 for hippocampus when compared with mice treated with WT leaf extracts and unfed. AD, Alzheimer's disease; CTB, cholera toxin B subunit; MBP, myelin basic protein.

 

 

 

The University of Pennsylvania (where the research was done) filed a patent on it last here.

 

 

There is a brief comment and overview on the study here.

 

 

 

 

It should also be noted that the use of CTB as an antigen is already permitted by the FDA,9 and MBP is naturally found in the circulation, potentially allowing translational study of this technology at a rapid pace.

 

 

 

 

Edited by prophets, 13 December 2016 - 11:32 PM.

[Avatar of Horus]

The first-in-man clinical trial targeting Alzheimer's Tau protein
Karolinska Institutet, 12-Dec-2016
https://www.eurekale...i-tfc121216.php

 

Initial Results Reported from a Phase 1 Safety Trial of a Tau Vaccine

http://www.longecity...-a-tau-vaccine/

[mag1]

Anyone have any references for recent AD research for C. sporogenes.

wiki article below talks of inhibition of amyloid fibril formation and reduction in glial activation.

 

Would be very interested to know the risk of AD among those with C. sporogenes colonization

Also IPA supplementation? 

 

 

 

https://en.wikipedia...dium_sporogenes

 

http://www.dailymail...ncer-fight.html

Edited by mag1, 15 December 2016 - 07:24 PM.

[davis89x]

I'm not sure if this would be correct thread for posting this, but I could find any better, but if someone do, please move this where it would fit better.

 

The Science of Brain Health and Cognitive Decline | Eric Kandel - Youtube(7 min)
 

Spoiler

 

 

There are two major forms of learning: implicit or explicit or declarative and non-declarative.

0:13

The simple form of learning, which I studied in Aplysia, which holds true for all invertebrate

0:20

animals, is learning of perceptual and motor skills.

0:26

More complex learning involves the hippocampus requires conches participation and it involves

0:37

learning about people, places and objects.

0:40

So two different systems, implicit learning, which does not involve conscious participation,

0:48

involves a number of systems in the brain.

0:50

In the simplest cases just reflects pathways themselves, but in other cases it could involve

0:55

the amygdala for emotional learning, the basal ganglia for some motor tasks.

1:00

So these are a variety of systems, but the hippocampus is not in any fundamental way

1:06

involved.

1:07

In the learning of people places and objects it involves conscious participation and it

1:14

involves the hippocampus.

1:16

The hippocampus is not critical throughout the lifetime of the memory, but it's critical

1:20

for the initial storing and consolidation of the memory.

1:26

So these are two very fundamental systems.

1:28

Mammals have them both, invertebrate animals only have one.

1:33

Life long learning is extremely important and the more we learn about life span the

1:38

more important we realize it is.

1:41

First of all it's pleasurable.

1:45

Most people after a while realize when they acquire new knowledge about something that

1:51

it's really quite an enjoyable experience.

1:54

But also it's like doing exercise, in fact it's exercise of the brain.

2:00

It's good for you.

2:02

So as people age they're susceptible to one of two kinds of cognitive declines.

2:12

One is Alzheimer's disease, which begins in the 70s but becomes almost an epidemic when

2:20

people are in their 90s when almost have the populations has Alzheimer's disease.

2:24

And the other, which was only recently appreciated to be quite distinct from Alzheimer's disease,

2:31

is called age related memory loss.

2:35

The difference between Alzheimer's disease in the sense that it starts earlier, it starts

2:38

in mid life; it involves a different part of the brain it starts in the dentate gyrus,

2:44

Alzheimer's disease starts in the entorhinal cortex.

2:48

And it is prevented.

2:53

You can prevent it.

2:54

And also to some degree you might be able to reverse it.

2:57

The things that prevent it, the things that are prophylactically useful for it are social

3:04

involvement, cognitive involvement, learning new skills, learning a foreign language, physical

3:11

exercise, a good diet and good health, making sure if your blood pressure goes up that it's

3:17

controlled, that if you have diabetes that it's controlled, et cetera, et cetera, et

3:21

cetera, those things act importantly to reduce the likelihood and limit, essentially illuminate

3:32

age related memory loss, or at least significantly restrict it.

3:36

And what recently emerged as a result of a colleague of mine at Columbia Gerard Karsenty,

3:43

is that there is a new approach to this.

3:46

Karsenty found out that your bones are an endocrine gland.

3:50

They release a hormone called osteocalcin.

3:54

And osteocalcin acts on the testes and the ovaries, on the liver, acts on many organs

4:00

of the body, but it also acts on the brain.

4:03

And it acts on the brain to enhance memory storage.

4:07

It does other things as well, but it enhances memory storage and it enhances the memory

4:13

storage in young people but also enhances memory storage in all people.

4:21

And one of the reasons that exercise is important is because exercise builds up bone mass.

4:27

This is particularly important in the women where bone mass tends to decrease more dramatically

4:32

that in men, but it's important for everybody.

4:34

So when you exercise you increase your bone mass, you increase osteocalcin and you improve

4:42

age related memory loss.

4:45

So recently Karsenty has done a very interesting experiment, it's been known for some time

4:50

that if you take an old mouse that has age related memory loss, et cetera, et cetera,

4:56

et cetera, mice never get Alzheimer's disease they only get age related memory loss.

5:02

I found that that's one of the early clues that made me think it might be different from

5:05

Alzheimer's disease because you can have pure age related memory loss without having Alzheimer's

5:10

disease.

5:12

If you take an old mouse, which has age related memory loss, and cross perfuse it with a young

5:17

mouse that doesn't, that is take the blood out of it and give it to the blood of a young

5:23

animal, you rescue age related memory loss.

5:26

And Gerard Karsenty had found that one of the critical factors in young blood is osteocalcin.

5:32

So it fits in with the idea that exercise, which builds up bone mass it releases osteocalcin,

5:41

it has this rejuvenating effect on the brain.

5:47

Also together with Scott Small we analyzed some of the genetic changes that are involved

5:52

in age related memory loss and we showed that it involves a cascade that's involved in converting

5:58

short-term memory into long-term memory.

6:00

In earlier work I'd shown that when you convert short-term memory to long-term memory in almost

6:05

all systems it involves a particular alteration in gene expression.

6:10

A gene called CREB, cyclic AMP-responsive element binding protein, is activated.

6:18

And it acts not by itself but together with two other components, the CREB binding protein

6:23

and a protein called RbAB 48.

6:27

And Scott Small and I found that RbAB 48 is dramatically decreased in age related memory

6:32

loss.

6:33

And if you restore it you can to make an old mouse young, if you knock it out you can take

6:39

a young mouse and make it old.

6:42

So clearly we had very good evidence that we had identified at least part of a molecular

6:46

cascade that's important for age related memory loss and then we tested and we saw osteocalcin

6:52

acts on several places in the brain, but it also acts on this critical switch, it facilitates

6:57

the working of the switch.

 

Edited by YOLF, 22 December 2016 - 05:17 AM.

[Izan]

Alzheimer's hope in new memory-restoring drug

http://newatlas.com/...e-memory/47058/

[RWhigham]

Copied from my post in bioscience news

 

http://www.sciencedi...006295213007612  "Tau-aggregation inhibitor therapy for Alzheimer's disease" This article is great and has far more content than the title indicates. 

 

Thesis:

Short stable segments of tau form spirals called Paired Helical Filaments (PHF) which grow and spread similar to prions over a lifetime. The tau accumulation is classified by the Braak group from autopsies at all ages of life as stages I-VI. AD becomes apparent in stage IV. Stage I is common by age 50 but doesn't always progress. Stage II seems to always progress. Tau-accumulation can be prevented/reduced by Cinnamon, Aged Garlic, Virgin olive oil, Green tea, Curcumin, Panax Ginseng, and more. Tau aggregation drugs for progressive supranuclear palsy (PSP) failed because they attacked the hyperphosphorylation of PHF but did not affect the PHF core. (corollary AMPK's hyperphosphorylation of PHF is not the cause of AD) The tau-tau connections in PHF can be attacked without affecting the essential tau-microtubule connections. 

 

Contents:

1. The β-amyloid consensus in Alzheimer's disease

2. The tau aggregation pathology of AD

    2.1. “Alzheimer's disease”

    2.2. The composition of Alzheimer's neurofibrillary tangles

    2.3. Failure of phase 2 trials in progressive supranuclear palsy (PSP) and likely non-role for abnormal tau phosphorylation

    2.4. Truncated tau and its propagation

3. The epidemiology of tau aggregation pathology

4. Inhibition of tau aggregation for treatment and prevention of AD

5. Implications of potential efficacy of TAI therapy in AD

    5.1. Initiators of tau aggregation

    5.2. Role of β-amyloid in tau aggregation

    5.3. Implications for β-amyloid intervention trials

6. Conclusion

 

For more natural prevention of AD see https://www.ncbi.nlm...les/PMC3575183/  "Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease"

 

 

Edited by RWhigham, 02 January 2017 - 06:08 PM.

[ta5]

Here's a new article on Copper. But, nothing new to say really.

 

 

Chem Res Toxicol. 2017 Feb 6.
The Copper-2 Hypothesis for Causation of the Current Alzheimer's Disease Epidemic.

Brewer GJ.

Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries, but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveals the epidemic is a creature of the last century. That is the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community. Disappointing because these facts clearly point at an environmental change in the 20th century in developed countries as a major factor in causing the epidemic. Some scientists have discarded the claimed rarity of the disease in the 19th century as incorrect, saying that Alzheimer's disease is a disease of aging, and the increasing lifespan of people accounts for the current high prevalence of the disease. But this cavalier attitude ignores historical data indicating there were many elderly people in the 19th century that weren't getting Alzheimer's disease with any significant frequency. In this review, after documenting that the observed assertions about historical and demographic facts are correct, evidence is amassed that the main environmental culprit causing the Alzheimer's epidemic is ingestion of divalent copper, or copper-2. The two sources of copper-2 ingestion are drinking water and multimineral supplement pills containing copper. The increase in copper plumbing use in developed countries parallels the increasing prevalence of Alzheimer's disease. It has been shown that enough copper is leached from copper plumbing in most households to cause Alzheimer's disease, using the Alzheimer's disease animal model studies as a guide to toxic levels. It is relatively easy to avoid or greatly diminish copper-2 ingestion by not using copper containing supplement pills, and testing drinking water for copper levels. If the copper in water is too high, a simple device can be put on the tap to remove copper.

PMID: 28161940

 

 

This author has several similar published articles, including this human trial on Zinc deficiency and [150mg] zinc therapy efficacy with reduction of serum free copper in Alzheimer's disease.

 

Given the above discussion of the critical roles of zinc in maintaining healthy neurons and the demonstration that AD patients are zinc deficient, it is logical to consider a trial of zinc therapy in AD. Interestingly, an uncontrolled trial of zinc therapy, both oral and parenteral, was carried out in 1992, with reportedly dramatic positive effects [20]. The uncontrolled nature of this study detracts from its significances, but it is puzzling that this very positive study has not been followed up. The probable reasons are that controlled drug trials are expensive and that the lack of a patent on zinc makes it unattractive to drug companies. In addition to the former human work, there has been a positive animal study, in which zinc supplementation caused improvement in an AD animal model [21].

[...]

The very exciting results are shown in Table 1. With ADAS-Cog, a more positive change over the 6-month period indicates deterioration, and the placebo group deteriorated +1.27 points while the treatment group actually improved −0.76 points with a statistically significant difference at P = 0.037. With CDR-SOB, a more positive change again indicates deterioration, and the placebo group deteriorated +0.87 points, while the treatment group deteriorated significantly less (P = 0.032). With MMSE, a negative change indicates deterioration and the placebo group deteriorated −1.0 points while the treatment group actually improved to +0.58 points, but results were not quite statistically significant at P = 0.067.

 

 

Could it be this simple?

 

[lumia]

Here's a new article on Copper. But, nothing new to say really.

 

 

Chem Res Toxicol. 2017 Feb 6.
The Copper-2 Hypothesis for Causation of the Current Alzheimer's Disease Epidemic.

Brewer GJ.

Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries, but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveals the epidemic is a creature of the last century. That is the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community. Disappointing because these facts clearly point at an environmental change in the 20th century in developed countries as a major factor in causing the epidemic. Some scientists have discarded the claimed rarity of the disease in the 19th century as incorrect, saying that Alzheimer's disease is a disease of aging, and the increasing lifespan of people accounts for the current high prevalence of the disease. But this cavalier attitude ignores historical data indicating there were many elderly people in the 19th century that weren't getting Alzheimer's disease with any significant frequency. In this review, after documenting that the observed assertions about historical and demographic facts are correct, evidence is amassed that the main environmental culprit causing the Alzheimer's epidemic is ingestion of divalent copper, or copper-2. The two sources of copper-2 ingestion are drinking water and multimineral supplement pills containing copper. The increase in copper plumbing use in developed countries parallels the increasing prevalence of Alzheimer's disease. It has been shown that enough copper is leached from copper plumbing in most households to cause Alzheimer's disease, using the Alzheimer's disease animal model studies as a guide to toxic levels. It is relatively easy to avoid or greatly diminish copper-2 ingestion by not using copper containing supplement pills, and testing drinking water for copper levels. If the copper in water is too high, a simple device can be put on the tap to remove copper.

PMID: 28161940

 

 

This author has several similar published articles, including this human trial on Zinc deficiency and [150mg] zinc therapy efficacy with reduction of serum free copper in Alzheimer's disease.

 

Given the above discussion of the critical roles of zinc in maintaining healthy neurons and the demonstration that AD patients are zinc deficient, it is logical to consider a trial of zinc therapy in AD. Interestingly, an uncontrolled trial of zinc therapy, both oral and parenteral, was carried out in 1992, with reportedly dramatic positive effects [20]. The uncontrolled nature of this study detracts from its significances, but it is puzzling that this very positive study has not been followed up. The probable reasons are that controlled drug trials are expensive and that the lack of a patent on zinc makes it unattractive to drug companies. In addition to the former human work, there has been a positive animal study, in which zinc supplementation caused improvement in an AD animal model [21].

[...]

The very exciting results are shown in Table 1. With ADAS-Cog, a more positive change over the 6-month period indicates deterioration, and the placebo group deteriorated +1.27 points while the treatment group actually improved −0.76 points with a statistically significant difference at P = 0.037. With CDR-SOB, a more positive change again indicates deterioration, and the placebo group deteriorated +0.87 points, while the treatment group deteriorated significantly less (P = 0.032). With MMSE, a negative change indicates deterioration and the placebo group deteriorated −1.0 points while the treatment group actually improved to +0.58 points, but results were not quite statistically significant at P = 0.067.

 

 

Could it be this simple?

 

The tone doesn't even sound like a review paper, more like a Clinical Practice paper.
 

[albedo]

The following study looks like an important step. One of the authors, Frida Fåk Hållenius, says:

 

"Our study is unique as it shows a direct causal link between gut bacteria and Alzheimer’s disease. It was striking that the mice which completely lacked bacteria developed much less plaque in the brain”.“The results mean that we can now begin researching ways to prevent the disease and delay the onset. We consider this to be a major breakthrough as we used to only be able to give symptom-relieving antiretroviral drugs.”

 

Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.

 

Gut bacteria may play a role in Alzheimer’s disease

http://www.lundunive...heimers-disease

[resveratrol_guy]

 

 

This author has several similar published articles, including this human trial on Zinc deficiency and [150mg] zinc therapy efficacy with reduction of serum free copper in Alzheimer's disease.

 

Given the above discussion of the critical roles of zinc in maintaining healthy neurons and the demonstration that AD patients are zinc deficient, it is logical to consider a trial of zinc therapy in AD. Interestingly, an uncontrolled trial of zinc therapy, both oral and parenteral, was carried out in 1992, with reportedly dramatic positive effects [20]. The uncontrolled nature of this study detracts from its significances, but it is puzzling that this very positive study has not been followed up. The probable reasons are that controlled drug trials are expensive and that the lack of a patent on zinc makes it unattractive to drug companies. In addition to the former human work, there has been a positive animal study, in which zinc supplementation caused improvement in an AD animal model [21].

[...]

The very exciting results are shown in Table 1. With ADAS-Cog, a more positive change over the 6-month period indicates deterioration, and the placebo group deteriorated +1.27 points while the treatment group actually improved −0.76 points with a statistically significant difference at P = 0.037. With CDR-SOB, a more positive change again indicates deterioration, and the placebo group deteriorated +0.87 points, while the treatment group deteriorated significantly less (P = 0.032). With MMSE, a negative change indicates deterioration and the placebo group deteriorated −1.0 points while the treatment group actually improved to +0.58 points, but results were not quite statistically significant at P = 0.067.

 

 

Could it be this simple?

The tone doesn't even sound like a review paper, more like a Clinical Practice paper.

 

ta5, I want to thank you for the link to Brewer's zinc defficiency study. Despite having read his previous bombshell copper-2 paper, I was unaware of the zinc paper. I always thought that free zinc simply counteracted free copper (i.e. non-ceruloplasmin-bound copper) in the blood. Apparently I didn't know the half of it.

While he concedes that this is indeed the case, and as a result copper uptake into the brain is reduced, zinc has direct bearing on neuronal function: (1) it helps to stop the firing action commenced by glutamate and (2) it prevents excessive neurclastic action by calcineurin. Unsurprisingly, his group found that AD patients are zinc-defficient, but only perhaps by 10% in the blood. He suggests that this is a delayed and understated indicator of neuronal zinc deprivation in the brain.

No, I don't think AD is "that simple", but this is another major lever in disease arrest. Personally, I wonder whether this explains why a small subset of people, including me, seem to benefit from zinc gluconate. I've said several times on this site that I observed this consistently, with no good explanation other than simple reduction of plasma copper. Still, in my case, that makes little sense because I drink filtered water and don't consume vitamin pills. And yet, the effect is as strong as it was years ago. This paper may explain why.

But there's more to it than that. As I've also stated previous in this forum, I get awful sleep deprivation from nut consumption. The more I eat, the worse it is. I would see flashes and random shapes with my eyes closed many years ago, and now I get that plus an aggravation in tinnitus. The worst offenders are cashews and almonds, which are particularly rich in glutamate. I've long suspected the glutamate connection, and even moreso recently, as I've observed that my tinnitus gets worse as I consume increasing amounts of protein, on my miserable ketogenic diet of the past 3 months -- despite it being touted as "the" brain health diet. And yet, most other people don't seem to have these problems with glutamate consumption, based on the feedback to my inquiries here.

I've also stated previously that I suspect a problem with zinc transport. Based on this paper, I would say that the problem I have, which is far from unique in the world, is based on impairment of zinc transporter 3 (ZnT3). Unfortunately, my 23andMe has no data, but yours might if it's a more recent assay.

I think I'll raise my zinc gluconate intake from 50 mg every other day, to 50 mg/d, and see what happens, knowing full well that zinc toxicity could ensue at some point. I was always puzzled by the fact that I seem to need levels in excess of the supposed tolerable upper limit in order to function better. This points back to ZnT3 being somehow impaired.

Granted, if this is in fact the problem, then the real solution is CRISPR. But considering that's not happening any time soon, especially considing the craniotomy that would be required, the best solution is to try to overload the zinc supply in the hopes of compensating for the genetic impairment. I should note that, based on Brewer's notes, the best policy would be to feed oneself zinc in small doses throughout the day, for instance by splitting pills apart and eating the fragments just prior to meals.

The trial of Adeona's time-release zinc pill, which appears never to have been commercialized, was widely regarded as a failure, as it barely improved mental status scores over 6 months. However, as Brewer pointed out, the study was quite successful if one looked at only patients over 70. Nevertheless, I would expect that the therapy would be effective at maintaining white matter volume in individuals with ZnT3 impairment who have not yet developed AD. To me, this is more exciting than a drug that provides a big temporary boost to MMSE, which is facilitated by neurotransmitter tweaks, but does not affect underlying disease progression. The promise of zinc in this particular genetic population is that, if dosed properly, it could shut down runaway glutamate and calcineurin. (Incidentally, this also explains why excessive zinc causes temporary cognitive impairment in individuals with normal zinc transport: it simply shuts glutamate down prematurely, inhibiting sufficient firing.)

And yes, it's definitely a clincal practice paper, which is why, all else being equal, I take it more seriously than a petri dish study.
 

[mag1]

Yeah, once you have been around awhile you keep seeing the same authors publishing the same research for decades and decades.

This probably has at least something to do with mainstream society simply ignoring the findings of the research community.

 

Here's a group that has been going on about copper-2 AD for a few decades.

When will we say that's probably right and actually recognize a new clinical entity of Copper AD.

 

Squishing everyone into a broad diagnostic label such as Alzheimer's dementia will blur

disease complexity and make actually finding effective treatments much more difficult.

Some might not like seeing a fragmentation of the potential market, though we continue

to head directly into a dementiacastrophe in the 21st century and the only way out might

be to listen more to those who have done their homework. 

 

https://www.ncbi.nlm...pubmed/26758278

[Der Springende Punkt]

Years ago Brewer conducted a clinical trial against Alzheimer's with a specific zinc product. It failed like every other candidate. Since then he is producing paper after paper about copper and Alzheimer's.

[mag1]

The trial seems to have been a qualified success. Clearly younger subjects will simply obscure any positive cognitive benefits because they will usually not have much cognitive decline anyways.

 

It also quite notable that the subjects in the study were not selected to have Copper Alzheimer's: inclusion into the study only required the somewhat nebulous diagnosis of Alzheimer's. Some Alzheimer's trials have found that 30% or more of Alzheimer patients do not have Alzheimer's. The study might have selected patients on the basis of ATP7B variants etc. perhaps this would have increased the treatment effect. 

 

https://www.ncbi.nlm...?tool=pubmed#B6

 

A few points of interest.

 

1. The trial stopped all supplement use in all subjects. People are probably more exposed to copper supplements than zinc (??) so one might expect that the entire study group would experience a net positive for the study. This perhaps might obscure the reported benefit (??).

 

"Since elderly people tend to take a variety of supplements, many of which contain copper or zinc, we halted all supplement use beginning 30 days prior to the study, the first time that has been done in studying AD patients, to our knowledge."

 

2. The treatment doubled serum zinc levels. This could explain some of the cognitive benefit they saw.

    However, the serum free copper levels only fell by 20%.

 

    It was not mentioned in the article that free serum copper levels of 31 μg/dL are considered elevated.

    The reference range is 10-15 μg/dL.

    In Wilson's disease the aim is to go to 10 μg/dL or lower.

 

    Research has found that elevated free serum copper levels are related to Alzheimer cognition changes.

    I would be very interested to see a study that manipulated both the zinc and copper levels into their reference ranges.

    With copper perhaps dietary changes or other therapeutic interventions could be tried. 

    (Might be as simple as using dietary metal chelators such as ECGC

     https://www.ncbi.nlm...ubmed/26775960 )

 

"We also reached our end points with serum zinc and serum free copper. In the placebo group, baseline serum zinc was 70.8 μg/dL, and 6 months later, it was 75.3 (P = 0.153). In the zinc treatment group, baseline serum zinc was 76.4, and 6 months later, it was 151.8 (P = 0.002). Regarding serum free copper in the placebo group, baseline serum free copper was 34.8 μg/dL, and 6 months later, it was 34.9 (P = 0.486). In the zinc-treated group, baseline serum free copper was 37.0, and 6 months later, it was 30.8 (P = 0.004). So, zinc deficiency was very effectively eliminated and serum free copper was very significantly lowered by zinc therapy."

 

"by reduction in the level of non–ceruloplasmin-bound copper in the serum. With adequacy of treatment, this should decrease to 10 μg/dL or lower. Inadequate treatment or lack of compliance is usually associated with a level above 25 μg/dL. In the context of chelation therapy, urinary copper excretion initially exceeds 1000 μg/day and, subsequently, on maintenance treatment, should be between 250 and 500 μg/day."

 

http://www.cleveland...wilson-disease/

 

"Copper reference ranges are as follows:

Free serum copper: 1.6-2.4 μmol/L or 10-15μg/dL"

 

http://emedicine.med...087780-overview

Edited by mag1, 15 February 2017 - 06:22 PM.

[mag1]

res, I am with you on zinc. Of all the noots that I have tried,  zinc consistently has this near immediate effect for me.

It is like an instant intelligence enhancer.

 

Whatever amyloid or other brain fog that I might have it seems to lift very quickly after taking zinc.  

I only take it low dose and on occasion, though on those occasions it does seemed to have helped.

 

The study was using 150 mg doses of a special formulation of zinc for 6 months, that would be more than

I would be comfortable with, yet this was for Alzheimer patients.  

[Der Springende Punkt]

Suprise, suprise! The next big compound failed in phase 3. Merck's verubecestat study in mild to moderate patients was stopped due to futility: http://edition.cnn.c...ug-trial-fails/

 

Some scientists see the two verubecestat studies (a second study in prodromal patients is still running) as ultimate proof/disproof of the amyloid hypothesis.

[resveratrol_guy]

I think mag1 is right: the zinc trial was a hidden success, but it will never be worth the money to prove that rigorously. Nevertheless, thanks to ta5's paper, I've come to a significant personal realization about the relationship between zinc, glutamate sources, and one's success or failure with the ketogenic diet. It's here.

[deetown]

Has anyone had any luck or interest in acquiring the M13 Phage?

[Der Springende Punkt]

Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

Fujino T¹, Yamada T², Asada T³, Tsuboi Y⁴, Wakana C⁵, Mawatari S⁶, Kono S⁷.

Author information

Abstract BACKGROUND:

Plasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI).

METHODS:

The study was a multicenter, randomized, double-blind, placebo-controlled trial of 24weeks. Participants were 328 patients aged 60 to 85years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945.

FINDINGS:

Of 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20≤MMSE-J≤23) and MCI (24≤MMSE-J≤27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P=0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77years in the treatment group, and the between-group differences were statistically significant in females (P=0.017) and in those aged below 77years (P=0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group.

INTERPRETATION:

Oral administration of scallop-derived purified Pls may improve cognitive functions of mild AD.

FUNDING:

The Japanese Plasmalogen Society.

 

https://www.ncbi.nlm...pubmed/28259590

[DareDevil]

I though useful to post this also in this thread (from the Pentraxin's web site):

 

Strong experimental support for the DESPIAD trial of CPHPC in patients with Alzheimer’s disease

https://pentraxin.wordpress.com/news/

Hi Albedo,

 

This is interesting as there was marked improvement in other types of as seen in the dosage effectiveness after CPHPC of follow-up anti-SAP antibody dosed at 250mg to 650mg, see dosage chart on page 5 of the following study:

 

http://www.nejm.org/...6/NEJMoa1504942

 

FYI it was administered by intravenous infusion of 20mg/hour of CPHPC for 3 days to delplete circulating SAP followed by a single intravenous administration of IgG1 anti-SAP antibody followed by several day of CPHPC infusion 3 times daily.

 

The implications of this form of treatment are valuable in clearing all amyloid deposits and oral administration of these drugs would be feasible. If TAU is decidedly the cause of Alzheimer's versus Amyloid deposits, as mere symptoms, or If there is more recent information confirming or qualifying these findings critically, thanks for sharing.

 

DareDevil

 

Edited by DareDevil, 13 March 2017 - 12:48 PM.