What Causes Alzheimer's? Scientists Are Rethinking the Answer (quantamagazine.org) 41
"After decades in the shadow of the reigning model for Alzheimer's disease, alternative explanations are finally getting the attention they deserve," writes Quanta magazine — in a 10,000-word update on where we are now:
Three decades ago, scientists thought they had cracked the medical mystery of what causes Alzheimer's disease with an idea known as the amyloid cascade hypothesis. It accused a protein called amyloid-beta of forming sticky, toxic plaques between neurons, killing them and triggering a series of events that made the brain waste away.... Decades of work and billions of dollars went into funding clinical trials of dozens of drug compounds that targeted amyloid plaques. Yet almost none of the trials showed meaningful benefits to patients with the disease....
A stream of recent findings has made it clear that other mechanisms may be at least as important as the amyloid cascade as causes of Alzheimer's disease.... The emerging new models of the disease are more complex than the amyloid explanation, and because they are still taking shape, it's not clear yet how some of them may eventually translate into therapies. But because they focus on fundamental mechanisms affecting the health of cells, what's being learned about them might someday pay off in new treatments for a wide variety of medical problems, possibly including some key effects of aging.... While these alternate ideas were once hushed and thrown under the rug, now the field has broadened its attention.
The article explores the theory — derived from research on genetically-engineered mice — that neurons bulging with toxic accumulations of proteins and molecules could be mistaken for classic amyloid plaques outside cells. (But in fact "the extracellular amyloid plaques weren't killing the cells — because the cells were already dead.") Scientists are now also investigating lysosomes, cholesterol metabolism, and even the immune system.
To say that the amyloid hypothesis is dead would be overstating it, said Donald Weaver, a co-director of the Krembil Brain Institute in Toronto, but "I would say that the amyloid hypothesis is insufficient...."
By 2017, 146 drug candidates for treating Alzheimer's disease had been deemed unsuccessful. Only four drugs had been approved, and they treated the symptoms of the disease, not its underlying pathology. The results were so disappointing that in 2018, Pfizer pulled out of Alzheimer's research. A 2021 review that compared the results of 14 of the major trials confirmed that reducing extracellular amyloid did not greatly improve cognition....
The hypothesis took another hit last July when a bombshell article in Science revealed that data in the influential 2006 Nature paper linking amyloid plaques to cognitive symptoms of Alzheimer's disease may have been fabricated. The connection claimed by the paper had convinced many researchers to keep pursuing amyloid theories at the time.
A stream of recent findings has made it clear that other mechanisms may be at least as important as the amyloid cascade as causes of Alzheimer's disease.... The emerging new models of the disease are more complex than the amyloid explanation, and because they are still taking shape, it's not clear yet how some of them may eventually translate into therapies. But because they focus on fundamental mechanisms affecting the health of cells, what's being learned about them might someday pay off in new treatments for a wide variety of medical problems, possibly including some key effects of aging.... While these alternate ideas were once hushed and thrown under the rug, now the field has broadened its attention.
The article explores the theory — derived from research on genetically-engineered mice — that neurons bulging with toxic accumulations of proteins and molecules could be mistaken for classic amyloid plaques outside cells. (But in fact "the extracellular amyloid plaques weren't killing the cells — because the cells were already dead.") Scientists are now also investigating lysosomes, cholesterol metabolism, and even the immune system.
To say that the amyloid hypothesis is dead would be overstating it, said Donald Weaver, a co-director of the Krembil Brain Institute in Toronto, but "I would say that the amyloid hypothesis is insufficient...."
By 2017, 146 drug candidates for treating Alzheimer's disease had been deemed unsuccessful. Only four drugs had been approved, and they treated the symptoms of the disease, not its underlying pathology. The results were so disappointing that in 2018, Pfizer pulled out of Alzheimer's research. A 2021 review that compared the results of 14 of the major trials confirmed that reducing extracellular amyloid did not greatly improve cognition....
The hypothesis took another hit last July when a bombshell article in Science revealed that data in the influential 2006 Nature paper linking amyloid plaques to cognitive symptoms of Alzheimer's disease may have been fabricated. The connection claimed by the paper had convinced many researchers to keep pursuing amyloid theories at the time.
Re:the attention they deserve (Score:5, Interesting)
It's an affliction of elderly, wealthy white men.
this got me curious and is apparently not true at all, e.g. studies show that in the us african americans have actually 2x probability of manifesting the disease than white, followed by hispanics 1.5x, and the cause doesn't seem genetic but lifestyle related. they do get proportionally less diagnose and treatment than white, though.
https://aaic.alz.org/downloads... [alz.org]
https://www.nia.nih.gov/news/d... [nih.gov]
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this got me curious and is apparently not true at all
Indeed. Dementia is not only more common with non-whites, it is also more common in poor people.
Lower socio-economic status linked to dementia [alz.org]
It is also more common in women.
Women more likely to develop Alzheimers [harvard.edu]
Rich white guys are the least likely to be afflicted.
Re: the attention they deserve (Score:3)
nope, Asians in USA have even less, with south Asians the lowest. Rich Indian for the longtime fine brain!
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this got me curious and is apparently not true at all
Indeed. Dementia is not only more common with non-whites, it is also more common in poor people.
Lower socio-economic status linked to dementia [alz.org]
It is also more common in women.
Women more likely to develop Alzheimers [harvard.edu]
Rich white guys are the least likely to be afflicted.
Oh, it's just his agist racist and sexist proclivities. Wishful thinking.
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As they get old, however, they tend to become cognizant of the fact that they are not immune to it. The thing that really gets people excited about Alzheimer's, is that the main cause (assuming there even is one main cause) is completely unknown. That leaves people feeling vulnerable. It also intrigues the sort of people who are fascinated by difficult and mysterious problems.
LOTS of research money gets poured into Alzheimer's. Not as much as can
Re: the attention they deserve (Score:1)
Re:the attention they deserve (Score:4, Interesting)
Why do I have to keep correcting people? That stupid fraud paper in 2006 did not establish the amyloid hypothesis, the amyloid hypothesis had existed quite strong for decades prior and is independent of what that paper claimed.
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That stupid fraud paper in 2006 did not establish the amyloid hypothesis
The fraud paper didn't establish the hypothesis but strengthened it. Many researchers were considering switching their focus, but the fraudulent evidence convinced them to stick with what now looks to be a dead end.
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To say that the amyloid hypothesis is dead would be overstating it, said Donald Weaver, a co-director of the Krembil Brain Institute in Toronto, but "I would say that the amyloid hypothesis is insufficient...."
It's been quite dead for people working with those with Alzheimer's for at least a decade. Including those working with people with Alzheimer's living in Toronto (there Donald Weaver is located).
Maybe he's got dementia?
Re: the attention they deserve (Score:2)
In addition to what znrt pointed to regarding the race connection to Alzheimer's, women are far more likely to get it than men (to the tune of 2x).
Lower socioeconomic status is also linked to higher rates of dementia, so it is not a disease of the rich, but of the poorer.
So not only are you wrong, you're exactly wrong. Rich white men are less likely to get it than other races, genders, and incomes. Rich white men may make more news when they have it, but that doesn't make them more likely to have it. Even s
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It's an affliction of elderly, wealthy white men. So this is a given. And it was recently revealed that many of the papers and even the current pathological paradigm are based on fraudulent research.
If only we could create some form of health based crypto sca^H^H^H investment opportunity...?
Racist, sexist and ageist much?
They're re-thinking the answer... (Score:1)
Because they forgot the first time they thought about it
The attention-getting dementia (Score:5, Interesting)
For those of us who've had loved ones pass from other forms of dementia, it's a bit disheartening to see this particular form get all the attention. We get it though. Alzheimers has one of, if not the longest, time period on average from onset to death with a particularly long period where the patient needs skilled care. It's not just the cost, it's the emotional toll on the caregivers. My mother had a non-Alzheimers dementia that only required 18 months of skilled care, and it was still agony. There was also the several year lead-up where it was a bit like having a mentally ill child.
When I realized we were dealing with this, I googled around and found there are perhaps dozens of dementias, and only one with a cure--a form where cerebro-spinal fluid builds up, temporarily causing reversible demential and gait disturbance which is resolved by installing a shunt to relieve the pressure.
All the other forms are incurable, and I hope that in the rush to crush Alzheimers they aren't left out. I don't think they are--I think the Alzheimers Foundation and others are looking in to them; but I really do have to question how well they're doing that.
Who knows? Even though they are separate conditions with apparently separate causes, there may be some cross-over benefits in treating the different ones.
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While the media may obsess over Alzheimer's, the medical community must deal with all dementia cases brought to them. It is likely that doctors and nurses would like to treat all forms of dementia just as badly as you. The question is: where goes the funding? That is where perhaps we have a problem. Alzheimer's attracts quite a bit of funding, squeezing some of the oxygen out of the room.
Re: The attention-getting dementia (Score:2)
I feel for you, and sorry you had to go through the experience of having a loved on with dementia. I also lost a loved one, but to Alzheimer's, a process that took about 7 years. It's heart wrenching and had me asking daily how it's possible that it's 2022 and we don't even have a medicine that makes a dent in it.
The most frustrating viewpoint that I came across during my experience is this fiction that people with dementia live in a fantasy world, where they are too incoherent to realize that something is
Dementia is evil (Score:2)
This is a terrible disease. I've had family waste away to cancer and muscular disorders, but Alzheimer's is the most cruel. I used to make jokes about dementia and forgetting things, but after seeing it firsthand, absolutely nothing about it is amusing.
My 95yo mother is in long term care with advanced Alzheimer's. She is past the paranoid delusion stage and now mostly just sits and stares blankly out into space. She definitely knows something is wrong though. It is the most agonizing thing to watch and I would not wish it on my worst enemy (not to mention long term care homes are extraordinarily depressing places in their own right, filled with people with all manner of serious issues. The caregivers who work there are wonderful though, and I'm profou
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That's why we have medical assistance in dying (MAID).
Though plenty of us would take matters into our own hands when we notice a serious decline, and take action while we are still able to be masters of our fate (and our place in the universe).
I don't fear death - just the road to it. Being a "pod person" with no real understanding of what's going on around me most of the time, that my existence is just a shell, is not for me. One of my sisters said "they look happy." Of course they do, humans reflexiv
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That's why we have medical assistance in dying (MAID).
Yes. I'm glad recent changes to the law (because the original one clearly did not fully live up the Carter decision) now allow advanced directives. I never want to go through what my mother is and am glad I have the ability to spell that out clearly ahead of time.
When my dogs can no longer "be" dogs, I have to put them down out of love. Damn hard just writing about it. People deserve at least as much consideration as a dog.
I hear you, and agree.
Misinformation (Score:5, Informative)
"The hypothesis took another hit last July when a bombshell article in Science revealed that data in the influential 2006 Nature paper linking amyloid plaques to cognitive symptoms of Alzheimer's disease may have been fabricated. The connection claimed by the paper had convinced many researchers to keep pursuing amyloid theories at the time."
There is subtle misinformation in both of those lines. First, that paper only claimed to have discovered a SPECIFIC form of amyloid called AB*56 and proclaimed it to be the cause of Alzheimer's in certain cases. It played no role in establishing the amyloid hypothesis, which has been around as the leading if not undisputed contender for many decades prior. Second, I highly doubt it convinced anyone to "keep pursuing amyloid theories." Amyloid theories were strong independent of that paper. Nobody had seen AB*56 before, and actually, for some time it was viewed with skepticism as to whether it even existed. Anyway, there are MANY other types of amyloid to choose from -- various misfolded ones, insoluble, pre-fibrils, mature fibrils, etc. Knowing/guessing which one or ones to target has been difficult. The amyloid hypothesis itself is not debunked by that study on AB*56 being a fabrication. The amyloid hypothesis is still quite strong in spite of some drugs failing because newer drugs are in the pipeline that target the various forms of amyloid -- some of which are showing promising results.
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You are really wrong here. The AB*56 paper confirmed that pursuing the amyloid hypothesis was worthwhile and that there was success to be had in doing so. Falsifying confirmation is at least as bad as falsifying the original research. The problem in this specific cases is that scientific misconduct by several people delayed the insight that things are more complex. These fraudsters very likely contributed to an earlier death for numerous people and should be held to account accordingly.
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People keep bringing up the beta amyloid thing solely because nobody has managed to figure out what *does* cause the disease, so they keep going back to "i
Hang the bastards (Score:2)
That fraud should be heavily punished. Lots of money, time, and lives lost.
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You beat me to it.
On behalf of my dear sweet spouse who died this year due to early-onset Alzheimers I hope those bastards die a slow, painful death... for the false hope they inspired as well as the money wasted chasing a fraudulent idea. This applies to any medical fraud.
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Indeed. Faking scientific results should always come with all your academic titles stripped and public exposure of what you did. But when it is medical research, things are worse. What happens instead is that this gets swept under the rug routinely because too many people are doing it and too many people depend on the criminals for funding, often by way of reviews on publications. When you look at the damage that scientific misconduct does, this is completely unacceptable.
For h pylori try greek yogurt and reuteri (Score:2)
Helicobacter pylori (HP) is a Gram-negative bacterium that colonizes the human stomach chronically. Colonization of HP in the gastric mucosa not only causes gastrointestinal diseases, but also is associated with extra-gastric diseases, such as idiopathic thrombocytopenic purpura and neurological diseases. Among neurological diseases, epidemiological studies have shown that HP infection increases the prevalence of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since HP does not invade the
Inflammation? (Score:2)
I thought I read that a leaky gut often also meant a leaky brain. That is, the few-cell-wide (or less) barriers that keep apart two "sides" malfunction, allowing bad stuff to get into the wrong areas. Inflammation of these tissues is a suspected culprit. (And imperfect food is a common cause of at least gut inflammation.) Once breached, the body takes
Metabolism (Score:5, Interesting)
It's primarily a metabolic disease centered on cellular insulin interacting with mitochondria. Keep your insulin very low to protect your brain.
Energy demand of neurons is huge.
Amyloid is like scar tissue. The damage was the laceration but later you only see the scar.
Re: Metabolism (Score:2)
That sounds really interesting. Do you have any supporting references from peer-reviewed literature that I could look at? Thanks!
Anecdotal evidence time (Score:3)
Of course, that means nothing, but i can see how complex a problem dementia is to address, as it might be caused by environmental factors early in life, but only manifests decades later, when those environmental factors are long forgotten. So many difficult to pinpoint and pursue avenues of inquiry.
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That was a popular idea for a while, back in the mid twentieth century, and received a lot of attention in the form of research grants.
Larry Niven's teleporter/gunk remover (Score:2)
Sure, it was a basic idea, but it seems it might have fundamentally been the right one.
https://en.wikipedia.org/wiki/... [wikipedia.org]