I must have misunderstood something. My understanding is that the pharmaceuticals provide a slight benefit for the patient for some relatively short period of time, but none of them significantly changes the trajectory of the disease. That certainly has been what I have seen with my dear family member. Is my understanding correct?
If so, then does it make sense to think that amyloid is the cause of the disease or just part of the disease? I think there is something else…what is causing the amyloid?
I have been following dementia issues and research for about 10 years, when I saw that she was changing. The ReCODE protocol is the only thing I have read about that has any long-term success. I couldn’t get the family on board, and the decisions weren’t mine to make, and it has been awful to watch the deterioration while the rest of the family fully embraces main stream medical’s pharmaceutical approach. No work required by the patient = no long term benefit for the patient.
And now there will be another pill to treat another symptom instead of doing the work to figure out what is wrong and then doing the work to make the required changes.
At one point, I summarized everything I knew into an email and sent it to the family, trying to drum up some support and enthusiasm for this program. I ended the email saying that people are recovering, and “all you have to do is be willing to change everything.” No takers.
Short story long, if it turns out I’m wrong, and this pill is a game changer, and people who take it recover from dementia for a significant period of time, then sure, I would micro-dose. I don’t think that will be the case.
Forum Survey: Will you microdose aducan?
Re: Forum Survey: Will you microdose aducan?
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Re: Forum Survey: Will you microdose aducan?
Slide up.
Thank you for commenting JD2020. It is always interesting to hear the perspectives of different posters.
I do not think it is correct to characterize the benefits as small or of short duration. This aspect of aducan therapy has been largely overlooked during most of the discussion. I think the problem is that the long term extensions are not blinded so this somehow invalidates their results. Yet, as seen from the phase 1 extension above the longer term benefit of aducan is actually fairly massive.
This figure looks at aducan out to 4 years; perhaps even longer term results have been posted.
I drew in the blue horizontal line at MMSE of -5 to illustrate the duration effect. The high dose 10 mg/kg patients had decline on MMSE of 5 at week 220. This same level of decline was reported for the placebo ~ week 100 (orange vertical line). This is truly a massive delay in progression: ~120 weeks. Of course the "placebo" is not a true placebo anymore after week 52. Once into the LTE (green bar above figure), placebo is actually receiving treatment. Therefore, the benefit is actually more than a ~120 week delay. Those speaking on behalf of dementia patient rights and their right to treatment have made note of these large benefits that accrue over time. This delay in progression would be expected to continue for years and years. Even with this figure we can start to imagine that the dementia is losing out to the patients' typical aging.
The pink horizontal line shows how much of a gap opens up between the 10 mg/kg and "placebo", through time. Once again this is not a true placebo because the placebo in the LTE is receiving treatment of 3 or 6 mg/kg. Pink line is at -10 MMSE which is moving towards moderate/severe dementing illness (the most difficult stage for caregivers).
I also drew in a "regression" slanting green line that tries to capture the true nature of the decline of the 10 mg/kg, while avoiding the shorter term ups and downs.
There is an enormous dataset of aducan treated patients from the long term extensions and then the follow-on extension (Embark) that has not been reported yet. Apparently, in moderately large samples of these patients all on high dose aducan, over a longish time, they have been fairly stable. While this issue has largely been obscure, it clearly is overwhelming importance to patients and caregivers. Providing substantially improved quality of life over ~120+ weeks is astonishing. Of course, so much of this commentary has not somehow escaped the attention of Biogen. It is more by FDA rules only certain aspects of the trials are considered open to polite scientific discussion. A non-blinded extension is then largely out of bounds. Fortunately, we are bound by such conventions. Also as I have mentioned elsewhere, given that tau imaging is now on the table, even the extensions can be thought of as blinded. People would not be able to somehow guess what their tau levels would be, and yet tau levels greatly condition the benefit of treatment. With this information the separation through time that we see between treated and placebo would likely greatly magnify. Those patients who never entered into the middle intermediate range of tau might never progress. That would obviously capture some attention.
Many products that the FDA approves costing upwards of hundreds of thousands of dollars might offer benefits sometimes for as limited as weeks (along with substantial side-effects). aducan appears to offer benefits of upwards of years with extended dosing.
It is especially fortunate that this extremely important question now has very substantial clinical samples that will definitively resolve the question. aducan has thousands of patient years of extended dosing; the leca phase 2 also has very substantial extended dosing;
dona Trailblazer Ext. probably others.
Also of note is that the side-effects of aducan were most prominent over the first few months of treatment; after these front-end loaded side-effects (ARIA etc.) the patient is presumably receiving mostly benefits and not much side-effects.
Thank you for commenting JD2020. It is always interesting to hear the perspectives of different posters.
I do not think it is correct to characterize the benefits as small or of short duration. This aspect of aducan therapy has been largely overlooked during most of the discussion. I think the problem is that the long term extensions are not blinded so this somehow invalidates their results. Yet, as seen from the phase 1 extension above the longer term benefit of aducan is actually fairly massive.
This figure looks at aducan out to 4 years; perhaps even longer term results have been posted.
I drew in the blue horizontal line at MMSE of -5 to illustrate the duration effect. The high dose 10 mg/kg patients had decline on MMSE of 5 at week 220. This same level of decline was reported for the placebo ~ week 100 (orange vertical line). This is truly a massive delay in progression: ~120 weeks. Of course the "placebo" is not a true placebo anymore after week 52. Once into the LTE (green bar above figure), placebo is actually receiving treatment. Therefore, the benefit is actually more than a ~120 week delay. Those speaking on behalf of dementia patient rights and their right to treatment have made note of these large benefits that accrue over time. This delay in progression would be expected to continue for years and years. Even with this figure we can start to imagine that the dementia is losing out to the patients' typical aging.
The pink horizontal line shows how much of a gap opens up between the 10 mg/kg and "placebo", through time. Once again this is not a true placebo because the placebo in the LTE is receiving treatment of 3 or 6 mg/kg. Pink line is at -10 MMSE which is moving towards moderate/severe dementing illness (the most difficult stage for caregivers).
I also drew in a "regression" slanting green line that tries to capture the true nature of the decline of the 10 mg/kg, while avoiding the shorter term ups and downs.
There is an enormous dataset of aducan treated patients from the long term extensions and then the follow-on extension (Embark) that has not been reported yet. Apparently, in moderately large samples of these patients all on high dose aducan, over a longish time, they have been fairly stable. While this issue has largely been obscure, it clearly is overwhelming importance to patients and caregivers. Providing substantially improved quality of life over ~120+ weeks is astonishing. Of course, so much of this commentary has not somehow escaped the attention of Biogen. It is more by FDA rules only certain aspects of the trials are considered open to polite scientific discussion. A non-blinded extension is then largely out of bounds. Fortunately, we are bound by such conventions. Also as I have mentioned elsewhere, given that tau imaging is now on the table, even the extensions can be thought of as blinded. People would not be able to somehow guess what their tau levels would be, and yet tau levels greatly condition the benefit of treatment. With this information the separation through time that we see between treated and placebo would likely greatly magnify. Those patients who never entered into the middle intermediate range of tau might never progress. That would obviously capture some attention.
Many products that the FDA approves costing upwards of hundreds of thousands of dollars might offer benefits sometimes for as limited as weeks (along with substantial side-effects). aducan appears to offer benefits of upwards of years with extended dosing.
It is especially fortunate that this extremely important question now has very substantial clinical samples that will definitively resolve the question. aducan has thousands of patient years of extended dosing; the leca phase 2 also has very substantial extended dosing;
dona Trailblazer Ext. probably others.
Also of note is that the side-effects of aducan were most prominent over the first few months of treatment; after these front-end loaded side-effects (ARIA etc.) the patient is presumably receiving mostly benefits and not much side-effects.
Last edited by J11 on Wed Jun 02, 2021 7:31 pm, edited 2 times in total.
Re: Forum Survey: Will you microdose aducan?
Time will tell. That would be great if it were a wonder drug and we had the magic bullet for this terrible disease. I am not holding my breath - but I will truly be glad if I am wrong in my doubt.
Re: Forum Survey: Will you microdose aducan?
The second part about whether there is more to it than amyloid is also becoming clearer to me. Firstly, it is important to remember the logic behind aducan's development. aducan was reversed engineered by looking at healthy agers and then finding what anti-amyloid antibodies they had. These individuals must be true super-agers. They probably did not look for those who were the best at the 1% or even .1% level but at a truly extreme level of selection. They looked at elite cognitive agers. In a sense we already know that aducan works and that it completely prevents dementia from occurring because these super-agers had natural aducan and they remained dementia free. This is a powerful strategy for developing pharmaceuticals which is difficult to convincingly rebut.
These super-agers were chosen exactly because they did not develop dementia into advanced age. What was different about them? They naturally produced aducan in tiny doses throughout their lives. They did not need gram scales doses once they accumulated massive amounts of amyloid and were showing signs of symptomatic cognitive impairment: they didn't accumulate amyloid -- they didn't exhibit cognitive impairment. For them basically lowering amyloid throughout life prevented amyloid and it prevented cognitive decline. It is extremely exciting to realize that we could be only days away from a new era in aging in which everyone could become a super-ager by simply injecting homeopathic doses of aducan. Stopping the Alzheimer's pandemic actually could be as simple as reducing amyloid levels early on in life. All of the complex brain problems that emerge along with AD could be then thought of more as downstream problems that amyloid causes.
The main reason why the extended benefits of aducan have not been made more clearly obvious is that so little has been reported about them. Do they always have these FDA discussions with treatments without peer reviewed research and without fuller disclosure of the LTEs? It is not easy having a fact based discussion when the facts have been so thoroughly unreported.
Within the context of an 18 month AD trial it is very difficult to actually demonstrate substantial improvements. In the EMERGE and ENGAGE trials this was partly a result of choosing 80% MCI patients. In many of the trials these patients have not shown large treatment effects, probably because they are somewhat too early to even show decline. Yet, the early AD patients have shown larger treatment effects on aducan.
These super-agers were chosen exactly because they did not develop dementia into advanced age. What was different about them? They naturally produced aducan in tiny doses throughout their lives. They did not need gram scales doses once they accumulated massive amounts of amyloid and were showing signs of symptomatic cognitive impairment: they didn't accumulate amyloid -- they didn't exhibit cognitive impairment. For them basically lowering amyloid throughout life prevented amyloid and it prevented cognitive decline. It is extremely exciting to realize that we could be only days away from a new era in aging in which everyone could become a super-ager by simply injecting homeopathic doses of aducan. Stopping the Alzheimer's pandemic actually could be as simple as reducing amyloid levels early on in life. All of the complex brain problems that emerge along with AD could be then thought of more as downstream problems that amyloid causes.
The main reason why the extended benefits of aducan have not been made more clearly obvious is that so little has been reported about them. Do they always have these FDA discussions with treatments without peer reviewed research and without fuller disclosure of the LTEs? It is not easy having a fact based discussion when the facts have been so thoroughly unreported.
Within the context of an 18 month AD trial it is very difficult to actually demonstrate substantial improvements. In the EMERGE and ENGAGE trials this was partly a result of choosing 80% MCI patients. In many of the trials these patients have not shown large treatment effects, probably because they are somewhat too early to even show decline. Yet, the early AD patients have shown larger treatment effects on aducan.
Last edited by J11 on Wed Jun 02, 2021 6:10 pm, edited 1 time in total.
Re: Forum Survey: Will you microdose aducan?
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Re: Forum Survey: Will you microdose aducan?
The above is another figure that I like posting and reposting and then posting again. It shows how much of a cognitive benefit there is to removing more amyloid. The 103 patients with 1 sd or more amyloid removal had a 3 point advantage on those with less than 1 sd amyloid removal. A similar figure for the phase 3s would have been welcome. However, the figure provides an indication that there can be large cognitive benefits even over the short term for removing more amyloid. There is much research that has been reported about strategies that could be used to amplify amyloid removal once an anti-amyloid such as aducan were on the market. The benefits of aducan could continue to be enhanced once it is on the market.
Re: Forum Survey: Will you microdose aducan?
circ, I have been perusing through my full genome scan: it is quite informative and yet also somewhat scary. For example, I hit every single risk genotype for Crohn's it was amazing. I will want to do the multinomial probability calculation for this result. For the 49 loci that increased Crohn's risk somehow I managed to hit all 49 of them (though fortunately not homozygously). There were 20 loci that reduced risk; astonishingly I did not hit a single one of these risk reducers. I achieved a near perfect score for risk for Crohn's. Of course, the hidden statistical fallacy that is involved here and was noted in the aducan documents is that you need to be aware of the multiplicities involved. Basically they took hundreds of polygenic scores and they reported those scores that were the most extreme. My polygenic risk score for Crohn's approached the 100th percentile. What is quite odd though is that I have never noticed any particular problem with Crohn's. Many of the diseases that I am supposedly at extreme risk likewise are largely unknown to me.
I expect that many of these non-diseases might in time become recognized as treatable problems; even though I do not clearly have any symptoms for them. Basically, the future will convert the worried well into the worried unwell simply through the results of genotyping?
It is now all too obvious to me now that the idea of misplaced genetic agnosticism is no longer even worth entertaining. The cheery advice for those with these genetic risks that even not so long ago might have been "Oh, all you need is think positive thoughts and eat a balanced diet" no longer can be understood to be realistic. Some people are just at profoundly high risk of certain outcomes due to their genes and we have arrived in a world where this will need to be accepted. Totalitarian egalitarianism simply hurts too many people and is completely incapable of actually achieving an equalized outcome. Genetic technology likely will achieve such a result through time, though in this initial stage of genetic discovery diversities will be more prominent than unities.
There are some traits that I have even higher genetic risk than for Crohn's. Fortunately, I have almost no idea of what these others are all about. However, right near the top is Parkinson's. I am almost exactly at the top 100th percentile in risk. Strangely, again with Parkinson's I somehow managed to avoid genotyping for any of what looks to be dozens of risk reducing alleles. How is it possible to be that unlucky? I am very unsure what the plan will be if the problem is more of an AD/Parkinson's/lewy body dementia that we are looking at. One of our care helpers did remark that the dementia did seem mixed with motor symptoms. We had thought that this was more a seizure disorder, though perhaps it could also be thought of in motor terms. Within the apoe 33 constellation of dominant AD my understanding is that such a mixture likely is not that uncommon.
With epsilon 4, family's can rapidly cycle through dementia status within a generation or two. For many 44 genotype is a surprise to them. With 33 dominance it is more that very odd traits simply accumulate through time. This is what we have seen in our genomes.
A great deal of odd genotypes. Typical people want a very dull life trajectory; they do not want to deviate from "normal". We have Clotho variant, and a great many others on board. Not a dull genome. Given current genomic selection technology, much of this genetic diversity could be rapidly selected against; we could be dull too in about 2 generations.
I expect that many of these non-diseases might in time become recognized as treatable problems; even though I do not clearly have any symptoms for them. Basically, the future will convert the worried well into the worried unwell simply through the results of genotyping?
It is now all too obvious to me now that the idea of misplaced genetic agnosticism is no longer even worth entertaining. The cheery advice for those with these genetic risks that even not so long ago might have been "Oh, all you need is think positive thoughts and eat a balanced diet" no longer can be understood to be realistic. Some people are just at profoundly high risk of certain outcomes due to their genes and we have arrived in a world where this will need to be accepted. Totalitarian egalitarianism simply hurts too many people and is completely incapable of actually achieving an equalized outcome. Genetic technology likely will achieve such a result through time, though in this initial stage of genetic discovery diversities will be more prominent than unities.
There are some traits that I have even higher genetic risk than for Crohn's. Fortunately, I have almost no idea of what these others are all about. However, right near the top is Parkinson's. I am almost exactly at the top 100th percentile in risk. Strangely, again with Parkinson's I somehow managed to avoid genotyping for any of what looks to be dozens of risk reducing alleles. How is it possible to be that unlucky? I am very unsure what the plan will be if the problem is more of an AD/Parkinson's/lewy body dementia that we are looking at. One of our care helpers did remark that the dementia did seem mixed with motor symptoms. We had thought that this was more a seizure disorder, though perhaps it could also be thought of in motor terms. Within the apoe 33 constellation of dominant AD my understanding is that such a mixture likely is not that uncommon.
With epsilon 4, family's can rapidly cycle through dementia status within a generation or two. For many 44 genotype is a surprise to them. With 33 dominance it is more that very odd traits simply accumulate through time. This is what we have seen in our genomes.
A great deal of odd genotypes. Typical people want a very dull life trajectory; they do not want to deviate from "normal". We have Clotho variant, and a great many others on board. Not a dull genome. Given current genomic selection technology, much of this genetic diversity could be rapidly selected against; we could be dull too in about 2 generations.
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DoubleBond
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Re: Forum Survey: Will you microdose aducan?
Yes, I would microdose - but I doubt it will be feasible because for me the price of the drug (assuming it is accepted) will be many thousands of dollars per year, and I doubt insurance will cover it. I would argue that that kind of money if directed towards supplements and lifestyle interventions could provide even more benefits.
Re: Forum Survey: Will you microdose aducan?
Thank you for your reply DoubleBond.
With other posters on this thread I have engaged them in argument; I will refrain from doing that again as a survey is typically more about asking people what they think and not debating the point excessively.
Yet, for the actual cost of microdosing it might be fairly reasonable; the mouse dosing was ~1,000 fold less than therapeutic doses. The question of dosing is somewhat unclear for humans. The high marginal rate of amyloid clearance for the dollar for microdosing might offer a compelling incentive to consider such a strategy.
With other posters on this thread I have engaged them in argument; I will refrain from doing that again as a survey is typically more about asking people what they think and not debating the point excessively.
Yet, for the actual cost of microdosing it might be fairly reasonable; the mouse dosing was ~1,000 fold less than therapeutic doses. The question of dosing is somewhat unclear for humans. The high marginal rate of amyloid clearance for the dollar for microdosing might offer a compelling incentive to consider such a strategy.
