Alzheimer's breakthrough

[Jarhyn]

“High Soluble Amyloid-ß42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations” by Andrea Sturchio, Alok K. Dwivedi, Tarja Malm, Matthew J.A. Wood, Roberto Cilia, Jennifer S. Sharma, Emily J. Hill, Lon S. Schneider,Neill R. Graff-Radford, Hiroshi Mori, Georg Nübling, Samir El Andaloussi, Per Svenningsson, Kariem Ezzat, Alberto J. Espay and the Dominantly Inherited Alzheimer Consortia (DIAN), 16 September 2022, Journal of Alzheimer’s Disease.
DOI: 10.3233/JAD-220808

According to an article my husband linked me, new research has pointed to a particular culprit in age related dementias: that the plaque is just the artifact of events that decrease soluble forms of protein, and that it is the lack of the protein, not the presence of the plaque, that is toxic.

The article:

Shocking Study Finds Decreased Proteins – Not Amyloid Plaques – Cause Alzheimer’s Disease

New research on patients with mutations published in the Journal of Alzheimer’s Disease. Contrary to a prevailing theory that has been recently called into question, new research from the University of Cincinnati (UC) bolsters a hypothesis that Alzheimer’s disease is caused by a decline in levels o

scitechdaily.com

 

[Loren Pechtel]

I have recently seen another report suggesting that the amyloid plaques are a symptom, not a cause, but suggesting that it was the immune system going amok that caused it.

 

[Jarhyn]

I have recently seen another report suggesting that the amyloid plaques are a symptom, not a cause, but suggesting that it was the immune system going amok that caused it.

Specifically, the immune system run amok does cause amyloid beta to form plaques.

The immune system run amok is a trigger in that model, but specifically because it causes plaque precipitation and decreases in soluble amyloid beta.

It's not an inconsistent result.

Notably the article mentions a drug that increases amyloid beta levels in the activity of plaque removal, and that this has shown positive results in Alzheimer's patients, while measures which reduce plaques by eliminating amyloid beta caused acceleration of Alzheimer's.

In this way it's more a byproduct of the causal event, the precipitation of avalable amyloid beta levels onto plaque formations.

 

[rjh01]

There have been many promising treatments, however, none have been proven to work.

 

[southernhybrid]

I think we knew about this for quite awhile. In fact, there was a group of nuns that were studied sometime ago, who had amyloid plaques but no symptoms of dementia.

I found an article from over 5 years ago, that talks about a small study that confirmed this.

https://www.statnews.com/2016/11/14...ences at the University of Texas, San Antonio.

The researchers analyzed the brains of eight people who died in their 90s and who had excellent recall until then. Three of the eight brains had the defining amyloid plaques and tau tangles of Alzheimer’s, yet somehow were “immune to [their] effects,” said neurologist Changiz Geula, of Northwestern University Feinberg School of Medicine, who led the study and presented the results at the annual meeting of the Society for Neuroscience in San Diego. “What’s significant about these findings is that they show there can be high densities of plaques and tangles in the brains of some elderly individuals who are cognitively normal or even superior.”

Although the study was small and preliminary, outside scientists were impressed. “This is an exciting paper,” said Dean Hartley, director of science initiatives at the Alzheimer’s Association, adding that Geula and his colleagues were “producing very solid work.”

I cared for the victims of AD for at least half of my nursing career. None of the drugs that were supposed to slow down the degeneration ever worked. My own 97 year old mother is a victim of the disease, but she was very sharp until she was 89. Plus, there are several other types of dementia that are just as bad, if not sometimes worse. We have a long way to go, I'm afraid, before we find any treatment that slows this awful disease, as well as the various other types of dementia, like frontal lobe and Parkinson's dementia etc.

Plus, AD can affect very young people, and early onset AD, as it's known usually has a strong genetic component. I had two patients in their early 40s who died of AD. I read a book about an entire family that acquired the disease while in their 30s. It's sad, regardless of the cause. So far, there isn't any strong evidence that late onset AD has a genetic component.

 

[Jarhyn]

There have been many promising treatments, however, none have been proven to work.

You might want to read the article, because it does mention one that has, recently, worked.

This is in fact part of the research referenced in the OP, and indicating toxicity not from a buildup but from a drawdown caused by the secondary buildup.

I think we knew about this for quite awhile. In fact, there was a group of nuns that were studied sometime ago, who had amyloid plaques but no symptoms of dementia.

I found an article from over 5 years ago, that talks about a small study that confirmed this.

https://www.statnews.com/2016/11/14/alzheimers-brain-amyloid-plaque/#:~:text=Previous studies have shown that some people with,Sciences at the University of Texas, San Antonio.

The researchers analyzed the brains of eight people who died in their 90s and who had excellent recall until then. Three of the eight brains had the defining amyloid plaques and tau tangles of Alzheimer’s, yet somehow were “immune to [their] effects,” said neurologist Changiz Geula, of Northwestern University Feinberg School of Medicine, who led the study and presented the results at the annual meeting of the Society for Neuroscience in San Diego. “What’s significant about these findings is that they show there can be high densities of plaques and tangles in the brains of some elderly individuals who are cognitively normal or even superior.”

Although the study was small and preliminary, outside scientists were impressed. “This is an exciting paper,” said Dean Hartley, director of science initiatives at the Alzheimer’s Association, adding that Geula and his colleagues were “producing very solid work.”

I cared for the victims of AD for at least half of my nursing career. None of the drugs that were supposed to slow down the degeneration ever worked. My own 97 year old mother is a victim of the disease, but she was very sharp until she was 89. Plus, there are several other types of dementia that are just as bad, if not sometimes worse. We have a long way to go, I'm afraid, before we find any treatment that slows this awful disease, as well as the various other types of dementia, like frontal lobe and Parkinson's dementia etc.

Plus, AD can affect very young people, and early onset AD, as it's known usually has a strong genetic component. I had two patients in their early 40s who died of AD. I read a book about an entire family that acquired the disease while in their 30s. It's sad, regardless of the cause. So far, there isn't any strong evidence that late onset AD has a genetic component.

You were in fact the poster I posted this "for", even while it was "for" everyone.

I know you work with a lot of late-stage cases, and research specifically on improving soluble Amyloid Beta rather than reducing insoluble Amyloid Beta plaques indicates that is a worthwhile treatment path to pursue, and that any information you get your hands on will percolate accordingly.

Wouldn't it be nice to see a SoHy post along the lines of "so, after the new Amyloid Beta treatments, _____ is actually more consistently recognizing _____ today, and no more outbursts over ______, 5 years passed standing them up at the diner this afternoon "

Or whatever.

 

[southernhybrid]

I appreciate that you were thinking of me when you posted the article, but what I posted certainly wasn't meant to be an insult. I'm sorry if you took it that way. To be honest, I'm not really sure what your last remark means. But, it's very easy when posting on social media to misunderstand each other. Sorry about that.

The problem is, at least from my perspective, is that there has been so much research regarding AD, and yet we haven't accomplished any effective treatments. I guess I just find that very frustrating, after being involved for so long with so many people who have suffered from AD. There are so many theories, risk factors, etc. that never seem to lead us to any conclusive evidence as to what causes this disease and what if anything can be done to slow it down. You are probably aware of the drug that was approved by the FDA about a year or so ago, without having much evidence to support its effectiveness. The drug is outrageously expensive. In fact, the big increase in Part B Medicare last year has been blamed on this drug. Most doctors are skeptical that the drug has much if any benefit for their patients.

I could be wrong, but it still seems to me that most AD is related to aging, as the biggest risk factor still seems to be lying past age 85. That is exactly the reason why my mother frequently told me that she didn't want to make it to 90.

I will go back when I have the time and reread your entire link, as I only scanned it earlier. I was in a hurry. Maybe I can add something more helpful later.

 

[southernhybrid]

I read your link again, Jarhyn, but it seemed to me as if a lot more research still needs to be done in this area. I'm not a highly educated scientist, but the article didn't include much information about the details of the research that went into the claim being made. Still, perhaps they are onto something that will eventually help those who suffer from AD and other types of dementia.

I would still like to know why this disease almost always impacts those of advanced age. We already know that early onset AD is a genetic issue, but we don't know why so many people over 85 are victims of AD.

 

[Jarhyn]

what I posted certainly wasn't meant to be an insult

I didn't interpret it as such. I was just hoping you would look into it deeply.

The problem is, at least from my perspective, is that there has been so much research regarding AD, and yet we haven't accomplished any effective treatments

I get that.

There's some hint at effectiveness of a particular amyloid plaque blocker, but as stated in the article, that blocker is unique in that it increases soluble Amyloid Beta.

It may have to do with a lifetime of poor amyloid beta levels owing to continual plaque development amid periods of immune stress. It may be that plaque growth is accelerative, or accelerative in certain situations.

One of the reasons for my publishing the original paper as the first opening of my post rather than the article was that I actually would like to see someone with access to such publications look at the research paper itself.

It has been linked in some cases to of all things the health of one's teeth, and the presence of oral plaques. It is also well known that dental issues accelerate with age, and this may ultimately be shown to be the primary "easiest domino" to target.

Again, this may be linked to the immune stress caused by oral infection or plaquing leading to amyloid plaquing.

Largely I agree that the article was light on details, however the case it laid out was IMO pretty solid: amyloid plaque treatments which reduce amyloid levels lead selectively to worse outcomes; amyloid plaque treatments which do not, do not decrease function; those with plaques and mutational factors but high measured A.b do not show symptoms; those who show symptoms show low A.b; a treatment which increases A.b (as an off-label effect) has actually started to show promise.

This, to me, points to a causative agent.

 

[Jarhyn]

.

a causative agent.

So, earlier today I asked myself after reading the article what amyloid beta actually does and why it's needed, and just looked it up: it is a membrane-forming repair protein.

It is additionally in this way implicated as an agent for which an insufficient supply would be causative of cumulative damage and decay of function.

If it gets plaquified instead of doing it's normal job of making a membrane where one is needed, function would suffer.

This would be especially true of any damage forms uniquely or solely addressed by amyloid beta.

 

[southernhybrid]

.

a causative agent.

So, earlier today I asked myself after reading the article what amyloid beta actually does and why it's needed, and just looked it up: it is a membrane-forming repair protein.

It is additionally in this way implicated as an agent for which an insufficient supply would be causative of cumulative damage and decay of function.

If it gets plaquified instead of doing it's normal job of making a membrane where one is needed, function would suffer.

This would be especially true of any damage forms uniquely or solely addressed by amyloid beta.

Do you know if this happens with other forms of dementia, like for example, frontal lobe dementia. I had a patient who had both AD and frontal lobe dementia. It was very sad, one of the worst cases I ever saw.

Thanks for sharing the info you found.

 

[Jarhyn]

.

a causative agent.

So, earlier today I asked myself after reading the article what amyloid beta actually does and why it's needed, and just looked it up: it is a membrane-forming repair protein.

It is additionally in this way implicated as an agent for which an insufficient supply would be causative of cumulative damage and decay of function.

If it gets plaquified instead of doing it's normal job of making a membrane where one is needed, function would suffer.

This would be especially true of any damage forms uniquely or solely addressed by amyloid beta.

Do you know if this happens with other forms of dementia, like for example, frontal lobe dementia. I had a patient who had both AD and frontal lobe dementia. It was very sad, one of the worst cases I ever saw.

Thanks for sharing the info you found.

No clue. I expect a lot would depend on the specific cofactors are for front lobe dementia.

As it is, I expect that there's going to be two primary forms of dementia, decay related and obstruction related.

AD appears to be decay related, caused by insufficient repair proteins, at least according to this. If there are proteins that primarily are impugned for repair in the front lobe, that might be part of it.

Alzheimer's was the one that got my grandpa and I am worried it's going to come knocking for my dad sooner than later.

If it does, I'm going to absolutely demand treatment in the vein of amyloid beta restoration, rather than plaque removal.

In the article it also does discuss some other dementias which involve protein plaquing, and possible imputement of low concentrations of soluble form rather than high concentrations of insoluble form proteins.

Even so, I'm not in the space so I couldn't say for sure.

 

[Loren Pechtel]

Notably the article mentions a drug that increases amyloid beta levels in the activity of plaque removal, and that this has shown positive results in Alzheimer's patients, while measures which reduce plaques by eliminating amyloid beta caused acceleration of Alzheimer's.

In this way it's more a byproduct of the causal event, the precipitation of avalable amyloid beta levels onto plaque formations.

That drug used a synthetic endpoint for it's approval testing--removing plaque. There's actually no indication that it helps Alzheimer's at all and if the plaques aren't the cause it's busted.

 

[Jarhyn]

Notably the article mentions a drug that increases amyloid beta levels in the activity of plaque removal, and that this has shown positive results in Alzheimer's patients, while measures which reduce plaques by eliminating amyloid beta caused acceleration of Alzheimer's.

In this way it's more a byproduct of the causal event, the precipitation of avalable amyloid beta levels onto plaque formations.

That drug used a synthetic endpoint for it's approval testing--removing plaque. There's actually no indication that it helps Alzheimer's at all and if the plaques aren't the cause it's busted.

The endpoint doesn't matter as much as whether the secondary effect of increasing solubility also is present, at least as predicted by the model of the study.

The plaques wouldn't be causal. The plaques would secondary.

The removal of plaques as treatment wouldn't be causal.

Imagine a cloud in the sky. Imagine some condition that is mitigated by clouds in the sky: the sun is too glaring.

Instead of connecting it to the clouds though, they connect it to snow on the ground: it happens that when there is a lot of snow in this place, it's because it all dumped out of the clouds. And the snow looks mighty shiny, even though the problem is really up in the sky.

If instead the people boiled the snow back into clouds whenever the snow fell rather than plowing it away, they would not see the problems that we imagine they see: it would be perpetually cloudy, and the people would be happy.

The endpoint of the medication was reducing plaques, but the secondary effect of increasing amyloid beta is of note, essentially "boiling up the snow to rebuild the clouds".

I would rather see investigation of options to just directly restore amyloid beta levels since targeting plaques for busting is rather indirect and stupidly inefficient.

 

[barbos]

So, what are the recommendation? eat more vegetables?

 

[Jarhyn]

So, what are the recommendation? eat more vegetables?

In some respects yes. Also, brush your teeth, and don't pick your nose.

Pretty much any kind of bacterial exposure or chemical imbalance to the brain that can cause soluble Amyloid Beta levels to decrease should be avoided to prevent AD. There are a number of other neuroprotective proteins as well associated with other diseases whose behavior, in the associated research, may point to a drop in soluble repair protein levels as a causal agent.

 

[barbos]

I think I read that stress is a significant factor in developing old age dementia.
Ronald Raygan and Margaret Thatcher both ended up with dementia.

 

[steve_bank]

Chronic stress increases levels of harsh hormones which can affect the heart and brain.

Long term stress results being in a permanent fight or flight condition.

What stress hormone kills brain cells?


Stress kills brain cells and decreases memory and learning ability. High cortisol levels kill newly created neurons in the hippocampus which ultimately decreases our memory and learning ability and can lead to more severe mental illnesses like Alzheimer's disease.Jun 1, 2021

 

[ZiprHead]

I sent this to my wife to give to one of her friends. Her friend has already lost one brother to AD and another is well into it. Everytime my wife's friend forgets something it makes her think "Is it now starting with me?" and it scares her to death.

 

[steve_bank]

'An ounce of prevention is worth a pound of cure.'