Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress toward a cure (2019)
statnews.com
statnews.com
Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug.
Or maybe the real problem is the excess emphasis on finding a drug in specific that can be commercially monetized. A single drug for a single cause of what is likely a complex process.
Amyloid and another protein (tau) accumulate in the brain due to sleep deprivation. Helping people get a good night's sleep -- without drugs -- would likely help, if only to stave it off in those at risk.
The problem is it won't create any razzle dazzle "unicorn" companies and newly-minted zillionaires.
One of the researchers in the article found that herpes simplex infection promotes the accumulation of amyloid. Her research was not irrelevant to the amyloid hypothesis. It was only irrelevant to an agenda to find a drug to treat amyloid.
As for other treatments, medicine basically boils down to surgery, drugs, and/or letting your body heal itself. The latter clearly doesn't work and for progressive diseases surgery generally isn't effective, so you're back to drugs.
Getting diagnosis and treatment for vitamin defficiency, hormonal imbalance, stomach microbiome, psycology related issues, and many other conditions simply does not happen unless patient does his own reading and pesters the doctor for treatment.
I had that bucketed in with letting the body heal itself.
I fully agree that there is a big gap between how medicine is delivered and what kind of overall care people need to be maximally healthy. It's what my current company does actually!
But with respect to diseases like Alzheimers, supportive care isn't going to cut the mustard in meaningfully impacting disease progression, you need drugs for that. And if you need drugs, the way the current regulatory regime operates, you need to have a shot at turning multiples of a billion in profit post-approval to pay back the development costs of the approved drug and all the drugs that failed to get approved.
People are dying right now. Giving them better sleep habits won't save them or meaningfully extend their lives. People are suffering in ways that I don't think you understand and I hope you never do.
Are doctors not already telling people to get good night’s sleep? Are healthy diet and exercise not already universally recommended? Do we not already warn people against smoking and excessive drinking? Have we not implemented sin taxes to disincentive these unhealthy behaviors?
Obviously these efforts, while beneficial are not even close sufficient. Thus there is a large unmet need for therapeutic intervention. Whoever is able to meet that need will be handsomely rewarded, and rightly so, because they will have meaningfully improved the health and quality of life of many many people.
None of these things are going to make anyone live to 150, and they sure arn't going to make you less frail at 90.
What we want are definitive treatments to both prevent and cure alheimers and given the options available in medicine id sure as hell prefer an expensive pharmacutical than something like brain surgery or weekly and exhausting procedures like dialysis.
People like to shit talk the pharma industry and theres a lot to shit talk it for but lets be clear here, a lot of pharmacutical solutions are god damned life changing miracles.
if someone deserves to be rich for their efforts it sure as shit should be people inventing medicine and not people in marketing or real estate or whatever.
I’ve never met a chronic inactive person who moved well as they aged.
We will need the pharma industry to treat Alzheimer’s and related conditions, but it is primarily lifestyle that we need to address to prevent it. Chronic lack of sleep will lead to all kinds of health issues, including dementia.
To a point. There are diminishing returns where genetics begins to play more of a factor.
For many people no amount of exercise is going to help them when they're 90 because they'll die before they turn 90. Jim Fixx[0] is the perfect example of this
Unless we develop a cure for Parkinson's disease I doubt Michael J. Fox[1] will live to 90, no matter how much exercise he does, because of the effects that disease has had on his body and the side effects from the treatments that he has received.
Another way to look at it is to substitute 90 with 100, 110, or 120. Or to think about what kind of exercise and healthy eating tips that you would recommend to a person with Down's Syndrome to help them live to be 90.
People who can should absolutely exercise and eat healthy food but that is no guarantee that they will live full healthy lives.
[0] https://en.wikipedia.org/wiki/Jim_Fixx#Death
[1] https://en.wikipedia.org/wiki/Michael_J._Fox#Parkinson's_dis...
Granted in both countries those who died after 75 lived presumably most of their life a traditional lifestyle with little influence of modern factors like junk food, TV at night, work stress etc. So we cannot conclude that those factors have no influence after 75th birthday. Still people should be rather skeptical about attributing to a particular factor really long life.
Doctors should ask how much sleep people are getting and recommend sleep studies if there sleep isn’t sufficient. There are also specific things that people can do to make it more likely that they get more and better sleep, and doctors should be going over these.
Home sleep trackers are much cheaper and easier to use these days, and it seems that there would be a benefit for everyone to wear one, at least part of the year, to have data to give to their doctor. We now have the means to really see if people are sleeping enough or not, and I suspect the issue in the past is that it is hard for people to accurately judge their own sleep performance.
It’s not just sleep length that matters, but rather sleep quality — specifically you want to make sure you are getting enough REM and slow wave sleep. So while we do need therapeutic interventions for people who already have Alzheimer’s, we really aren’t doing anything to prevent people from getting it in the first place.
I was listening to a podcast with neurophysiologist Louisa Nicola, and I swear she said that 95% of Alzheimer’s is now seen in people without a genetic predisposition to it. That is to say that people’s lifestyle decisions around sleep, food, and exercise are the issue. Here is a link to the podcast (no transcript unfortunately): https://podcasts.apple.com/us/podcast/whoop-podcast/id144550...
> I was listening to a podcast…
HN comments in a nutshell.
Think about that before you go off on your hobby horse about whatever stereotype you despise the most.
Anybody you could find on reddit or anywhere else can comment here if they find it and want to.
I think it was years before I even knew who Peter Thiel was, and I've never been to California in my life.
Why on earth do people (you're not alone, I know) prefer to assume that direction of causation, rather than that the underlying condition that leads to Alzheimer's causes sleep disorders too?
It's well known that sleep disorders are associated with other neurological or mental disorders.
I think there is a pervasive disease of thinking where people associate science and smart people with counterintuitive statements, so every obvious relationship gets inverted.
And can you answer the basic question of why sleep is even necessary at all?
Lack of sleep is eventually lethal, and I read a very interesting study a couple years ago that seemed to have a plausible mechanism and stunningly reasonable methodology, but I haven't heard anything about it since then. So I still don't know if it was fake or something, because it seemed like it should get a Nobel Prize. Although it used fruit flies so perhaps it didn't generalize.
It's generally known that after 3 or 4 days of total sleeplessness there is permanent psychological damage which is probably physiological in nature. IIRC There was a radio show host who hosted his show for several days straight as a stunt and it really messed him up.
Had to Google that, though it does sound temporary?
I didn't write that phrase precisely because people turn off their brains and learn nothing from it! It's become worthless.
The alternative to A -> B is B -> A, or C -> A and B.
You seriously think that running through those possibilities in your head is "dogmatism"?
Who then is the authority on which one of those is privileged and which require further research to validate, when they are all consistent with the evidence so far?
Pure speculation of course, but it seems possible that low quality sleep would impair this system.
How is that an explanation? Something has to drive the sleep disorder. It's too vague to be blaming for anything. It's not a thing.
May be there are multiple thing that drives sleep disorder and and then that causes Alzheimer.
Sleep studies can tell if you have sleep apnea, where you might "think" you had a full night's sleep, but it was disturbed by disrupted breathing.
So it might be worth getting one anyway. Hopefully the tech will get to the point where your fitness watch can do it all. The last sleep study kit I had was quite bulky and wearing it probably affected my sleep!
I really have the least amount of respect for sleep clinics I have had the displeasure of working with.
Sleep apnea is the most common sleep disorder, and it's easy to identify with equipment that you take home and use for a night. If you have it, there are different treatment options depending on the cause.
Other disorders are more difficult to treat, and sometimes they just don't have an answer. I'm still struggling with my sleep issues - they can describe it based on a full sleep study, but there's not a good categorization for it in the DSM, which means they can't even say if it's physiological, psychological, or a combination of the two. That makes it very hard to treat.
It wasn't the worst night of sleep of my life, but it definitely wasn't the best. The beds were cheap and simple, all the wires and electrodes were annoying, and the rain on the metal prefab clinic building was loud.
To be honest, I went because my partner complained about my snoring. If it meant a $3-4k bill, I would not have gone.
I never quite understood what you're supposed to do with all the information about when you fall asleep, when you awake, when you have REM.
Okay you can quantify how bad your sleep is (though I guess you can just feel that in your daily life to a large extent). But what's the next step? Prove to a doctor you actually have bad sleep bc they don't take your word?
Or are you supposed to make some life adjustments based on the information?
Or perhaps it’s just idiopathic/random/aging or environmental exposures that are less to do with lifestyle decisions. I’ve known plenty of people with Alzheimer’s and many of them tend to have had healthy lifestyles including healthy sleep - I would love to see any data that implicates meaningful risk reduction with “one weird trick” in sleep or diet - the common denominator was mostly old age.
I'm certainly aware there is a correlation, but unfortunately my life is not so structured that I can get sufficient sleep.
Would you have a reference for such a device? I assume that this is not an app in a phone, but something that actually measures the sleep phases?
Had a quick look at her Instagram - "80% of brain gray matter is modifiable by exercise so by hitting the gym you can now stave off Alzheimer's by 20 years"
> 95% of Alzheimer’s is now seen in people without a genetic predisposition to it
That's with our current knowledge of the genetic aspects of Alzheimer's, which probably isn't complete.
> That is to say that people’s lifestyle decisions around sleep, food, and exercise are the issue
Could be due to other reasons as well. Or most likely a combination of genetic + environmental. That's why these kind of illnesses (schizophrenia, depression) are so hard to crack, there's so many variables.
If the state is paying for and controlling your access to healthcare, it seems obvious that restricting unhealthy food or behavior as preventative healthcare would go hand in hand.
Even a drug addict who practices unsafe sex and riding motorcycles to do mountain climbing and ski down the slope deserves Healthcare when something bad happens to them, exactly as much as the fitness yoga guru.
We do have those restrictions. Consider the UK's Bradford Sweet Poisoning of the 1858 when the standard of putting gypsum as cheap filler in sweets instead of more expensive sugar lead to an accident of using arsenic instead, and lead to regulations on danerous behaviour by chemists and on the adulterations of foodstuffs - https://en.wikipedia.org/wiki/1858_Bradford_sweets_poisoning
Trans fats have been regulated, e.g. in Canada: https://en.wikipedia.org/wiki/Trans_fat_regulation#Canada
The UK has a sugary drink tax: https://en.wikipedia.org/wiki/Sugary_drink_tax#United_Kingdo...
And of course there are regulations on insect contamination, mould and fungal contamination, on use by dates, on permitted/banned additives and preservatives, on quality of packaging material, on preparation and handling of eggs; the most egregious "unhealthy food" that causes serious sickness and death quickly has been restricted. What's left is a lot of "compounds over a lifetime of it" kinds of things.
And, of course, public smoking bans are an unhealthy behaviour restriction, so are drug bans.
None have different tax rates for staple foods than for packaged snacks or fast food? None have regulations about labeling of food for health claims or disclaimers?
Because all of those things are common throughout all the European countries I'm familiar with, but maybe your list didn't include any European countries
They can also be popular with the electorate ("first they came for the smokers, and I didn't complain because I was not a smoker..") because people make moral judgments which is what you are complaining about, but that's not the reason economists favor them when it comes to advising politicians on tax policy.
Get over it and stop following libertarian religious sects, their teachings are only going to make you feel miserable and turn you into the annoying libertarian everybody dreads to meet in a party.
To then whine that fighting back is 'facist' or to suggest that you're so smart you are magically not influenced by any of this is an embarassment. Companies are permitted to operate in society by the collective will of the people, not by divine right. And the people collectively see that a company is taking the piss, they can change the arrangement to improve it. Saying "company, your behaviour is hurting people's collective health, you need to pay some more taxes to cover it" is one way of doing that. If the company then passes the tax increase to you in the form of higer prices, instead of lower profits, that's up to them.
The very framing of it as "sin tax" as if it's a personal failing and not a deliberate corporate abuse of our biological desires and limits, is a kind of victim blaming that anyone "immune to advertising" oughtn't be falling for.
> Are doctors not already telling people to get good night’s sleep? Are healthy diet and exercise not already universally recommended?
Yeah, most people know they need a good night's sleep. Most people who miss sleep aren't willfully choosing to skip it but responding to the constant pressure of things like work and school. Things like 24 hours shifts are awful. Which is to say, people actually need help getting sleep, they can't just be told losing sleep is bad.
Jobs that force a lack of sleep should be considered a health hazard and phased out by policy.
When all you have is a hammer something something.. In all seriousness, the majority of the developed world has solved the incentive problems with preventative care.
Wellness - dieticians, massage therapists, smart watches, etc - is a multibillion possibly even a trillion dollar industry.
> 12 hours work/day
> ads for unhealthy food
> lots of cheap tasty unhealthy food products in supermarkets
Have we really done the best we can as societies that the only thing left is to find a drug?
Within a system that promotes and often demands unhealthy lifestyles, we are doomed to scramble to find ways to battle emerging disease to enable our sick lifestyles.
It's not that individuals don't want to sleep, it's that oftentimes AD, PD, etc pts will present with sleep problems over 20 years before disease onset, and it isn't because these patients aren't trying. These patients will present with sleep disorders like REM sleep behavior disorder, and these seem to predate these disease onsets, but may also be a symptom of early stages of the disease.
TDLR: its not that people don't want to sleep, its oftentimes that AD pts present with sleep disorders decades before onset
isn't it still just a hypothesis that long term sleep deficits could be connected to dementia?
(1) Pathological levels of amyloid-beta and tau are present in cognitively normal individuals, and
(2) some individuals clinically diagnosed with AD do not have amyloid-beta pathology.
> Or maybe the real problem is the excess emphasis on finding a drug in specific that can be commercially monetized. A single drug for a single cause of what is likely a complex process.
And the proceeded to write this:
> Amyloid and another protein (tau) accumulate in the brain due to sleep deprivation. Helping people get a good night's sleep -- without drugs -- would likely help
And didn't see the irony at all?
Or reverse causation.
> Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug.
This discrepancy indicates part of the problem: the investigators narrowing the search for causes honestly believe in what they're doing.
The NIH review panelists really believe they're safeguarding the NIH budget, and the Pharma execs really believe they're wisely allocating their R&D budget.
We judge ourselves by our intentions.
We judge others by their actions.
This leads to people with evil actions judging themselves as good. “I didn’t want to do it. They gave me no choice.”
The rare few that do probably commit suicide. I'm reminded of some murderers that know what they are doing is wrong and knowing they're mentally unwell and end up killing themselves.
I wonder how you decided that. Most religions and many philosophers expound the virtues of good and why it matters. It goes by different names: loving kindness, metta, the Golden Rule, and a host of others.
If the concept exists for dominance alone, why do these religions and philosophers discuss it so much?
It's impossible for there to be an objective good or evil. As soon as there are no humans, then there is no good or evil, because it was subjective judgement, our emotions, all along, evolved to help us cooperate. Now, if it's not objective, then we know that people claiming it to be are either deluded or doing so in order to make their own will the norm (which philosophers love to do.)
> loving kindness, metta, the Golden Rule, and a host of others.
This confounds good and evil with ethics itself. Things like the Golden Rule, for example, can be deduced logically to generally be in all of our interests. As I said in my original comment, ethics can be reconstructed without superstition.
> If the concept exists for dominance alone, why do these religions and philosophers discuss it so much?
Obviously to get people to do what they wanted and that's exactly how it was always used by religious institutions which subsisted as parasites more often than not.
By that do you mean you present a theory about why people behave the way they do (whether or not they know it)? Or do you mean you can logically deduce the way people should behave?
> As I said in my original comment, ethics can be reconstructed without superstition.
Again, by that do you mean a description of what is observed or a normative proscription for behavior? Because I don’t see how the latter is possible without assuming meaning or purpose, which you would seemingly describe as “superstition”.
No, I guess you could do that, but I meant: Do you want to live in a situation where anyone is allowed to kidnap and torture anyone? It's not really in your interest, is it?
For example, he speculates that gluttony may be seen as a sin, because it was a way for disempowered people to feel superiority over people who had an abundance of food and wealth. If this frame is true (a big if), then one can be guided to not care about morality, and do what is in one's best interest.
Of course, there are good psychological reasons for why it is a bad reason to throw away morality. If one's identity is tied to being a good person, doing bad acts in conflict with one's identity can cause a lot of distress. There is also a "hedonistic treadmill" where one gets used to more and more wealth, and how additional wealth at a certain point doesn't make someone happier. Lastly, there are society reasons for why morality is important (e.g. the Golden Rule as you wrote); a low-trust society where no one is moral is not a healthy society to live in.
Counter-arguments aside, there is quite a bit of writing, also by philosophers, who argue that morality does exist for dominance alone (though I disagree with this, largely from a psychological rather than a philosophical perspective, due to lacking background to make rigorous-enough philosophical arguments).
These aren't counter arguments to what I said. They don't require concepts of objective good and evil, as I pointed out in my original comment and follow-up.
Most religions where spesifically used, abused and maybe invented to control the masses
Whence "should"? Why "equitable"? Why care about what everyone wants?
You trying to dominate somebody with these normative assertions?
Because anyone could be in anyone else's situation. You want norms that don't fuck you when you draw the short end of the stick.
> You trying to dominate somebody with these normative assertions?
I'm literally and transparently trying to convince you to do what I want.
Didn’t work. Partially because I don’t understand it.
Not necessarily. You’re claiming your worldview as universal.
It’s easy to imagine an ethics where strength and power are virtues and weakness is a moral failing, and the strong owe nothing to the weak.
So you're fine with a system where anyone is allowed to kidnap and torture you? That's in your interest? No, I didn't think so and you agree with me.
Lots of different areas, particularly in medicine, have slowed down or stagnated as a consequence of this. For example, the connection between immunity and cancer was obvious in the 1990s but it took many uphill battles to get funding for immunotherapies. Proponents of somatic mutations as a cause of cancer have typically taken most of the research funds and blocked alternative ideas.
Parkinson's, Alzheimer's, T1D, etc. have pretty similar stories.
Luckily less politically driven funding agencies and, ultimately, VCs are introducing some efficiency back into the system.
These days you can even raise a seed with no experimental data. That was extraordinarily unusual even well into the 2000s.
There are articles around discussing how in case of Alzheimer's it was impossible to get VC funding for immune ideas, even though they already had interesting evidence.
The same cabal was also blocking them.
I think you need to be an insider to realize how incredibly political most research in medicine is.
McKinsey separately reported that there has since been another boom in the biotech sector in the 2020s [1].
[0] https://www.science.org/content/blog-post/biotech-class-earl...
[1] https://www.mckinsey.com/industries/life-sciences/our-insigh...
Thanks, McKinsey, that's a great use of your consulting superpowers. Hey, was there a boom in artificial intelligence around 2015 as well? For $65,000 an hour, I'm sure you'll be happy to tell us.
Apparently VCs are clamping down on loose funding in the current climate, or thats not the case in biotech?
The problem with existing research is that it simply isn't that open to new ideas, particularly once funding streams are in place (because shifts in funding mean job losses, institutional impacts etc).
As you are pointing out, VC's often see monpolies as something to disrupt. So you'll take the taxi industry for example. A govt sanctioned monpoly with horrible service and low insurance limits. They'll make a play with something like uber.
Hotels -> airbnb / VRBO
And the list goes on.
You point out how VC's don't focus on short term profits. While I would agree, some however would argue that VC's should focus MORE on short term profits. I personally think too many money losing businesses are subsidized for way too long with VC money. In biotech that may be a good or necessary thing, but personally think this longer view is a bit of a negative.
Cancer research can appear very stagnant. Pharma companies and researchers funnel money into existing solutions and combinations of existing solutions which increase life expectancy by a few months, and quality of life by a few degrees. Not much foundational research on cures, and why should there be when every new drug which leads to slightly better outcome will be purchased by patients who will do anything to live a bit longer?
Now, how in the hell would VC be expected to improve that landscape? The ideal solution is a cheap therapy which cures cancer. Maybe a cancer vaccine. Where's the money in a 50 (or even 1k) tailored vaccine to cure a cancer when a slightly new combination of cancer drugs can cost $50,000 a month for the rest of the life of a patient?
I'd argue VC don't think long term for the benefit of anyone except themselves. They'll invest in a moonshot if it disrupts an industry for their benefit (e.g puts all taxi drivers out of work) but not if it eliminates an industry (e.g cancer research). There's way more money in funding a slightly different cancer drug.
Profit isn't revenue, for one thing. Does that hypothetical $50k/month treatment cost $49,999/month to manufacture? That's the story for a lot of drugs.
Whether or not the unit economics are $49,999/month or $49/month has no bearing on this. Treatments aren't commodities, they aren't apples at the grocer, where if the prices are too high, you just go to a competitor across the street.
Maybe Monsanto, Toll Brothers, and local governments should be funding cancer research?
More importantly, every major pharma has a compassionate use program that helps people who can't afford the drugs get them, through offsets and credits. I understand the desire to make pharma look like pure-evil profit mongers, but the reality is that this is not an easy business to be in.
It's pretty widely accepted the presence of this government-enforced monopoly significantly increases the price of many drugs.
The standard argument in favor of this is that it incentivizes R&D and we wouldn't have these drugs otherwise. I think it's debatable either way, but claiming these companies don't take advantage of this arrangement to increase prices is not true.
There is nothing wrong with patents "promoting the Arts and Sciences".
The problem in the US is that your largest buyers (Medicare, Medicaid, VA, Tricare) aren't allowed to properly use their buying power to push pharma companies on prices.
At the same time, there's very little restriction on pharma companies advertising directly to patients (banned in most nations) which puts pressure on GPs and specialists to over/off-label prescribe unnecessary pharma.
Prices in most countries are cheaper than the US because of that buying power that the government has, along with independent assessment of the value of new drugs and treatments in terms of QALY and cost/benefit to the people.
I work for a US biotech that is wholly owned by a EU pharma, not the US.
SpaceX against a huge established industrial base. That's going to be VC type funding, not traditional funding streams. We had govt initially doing everything they could to shut spacex out, doing block buys, trying to crush them on paperwork etc.
My complaint is simple. We know the current billions spent under current approaches have not cured a wide variety of illnesses. So what harm is there in spending some, relatively small amounts of money, on other ideas.
What's interesting is the reaction from folks like you, NIH, academics and others. It's vehement rejection. But why not instead demonstrate your approach results in a cure. The rejection is because you know you are sitting on nothing.
We see this with spaceX. Established astronomers are crying bloody murder. But this is in part because they are afraid. Their huge thirty meter telescope gravy train (decades of funding into their labs) is at risk of being totally trumped by cheaper access to space, where telescopes work great.
Established businesses tend to be risk averse. So in short, a role to play here for new ideas.
Note: Be careful about snarky comments, those are best avoided on HN, and can be a bit embarrassing in hindsight if you try to be snarky but inadvertently are correct and then have to try and walk back a point that you didn't mean to make.
Also please note that cancer vaccines have been tried but have failed for a few reasons. First, cancer cells are quite similar to normal cells, so cross reactivity is a problem. So, a typical approach is to to target “neoantigens” which are mutated cell surface proteins that are only on cancer cells. Not all cancers have neoantigens and they can mutate to stop expressing the neoantigen. Also tumors can express proteins that suppress or evade the immune system. PD-L1 blockers target one of the ways tumors do this.
All that to say, it’s not like people aren’t trying this stuff. It’s just really, really hard.
~15 years ain't so bad for the skepticism to make its way out of insider speculation to relatively well accepted (drug trials take a long time).
I don't have a skin in the game with the hypothesis (I'm actually biased against it) but it is worth noting that most of the drugs tried are antibodies, which introduces the confounding factor that all antibodies elicit an inflammatory oxidative response by locally catalyzing the conversion of oxygen to ozone (oxidative inflammation is thought to also be causal to Alzheimer's), so before we completely shut the book on it we might want to control for that.
VCs are clueless, but at least they are results-driven in a relatively neutral way, though they are going to be biased toward initial selection of idiotic investments. (You pick to fund something because it's a friend of a friend, a referral, social validation, etc.)
But not all of them right? So what exact merit does the statement hold?
I also did my PhD in a lab that rabidly believed in a hypothesis against all emerging data (it only didn’t matter that much because it was obscure). Even when my colleagues literally disproved the hypothesis my PIs undermined it while writing the paper with globs of ambiguity (just like you mentioned) and buried the result in Figure 5 instead of Figure 1, and made him never submit it to any prominent journal. All because this result made it look like they were idiots for 20 years for blindly believing a hypothesis with zero actual data. (If interested the hypothesis being IgG gets degraded in endothelial cells and that’s where the protein that salvages them works).
I’ve had front row seats for blinded belief in what you used to believe being what drives your science and focus. I am not yet prepared to forgive any lab that actually measurably put millions at misery because of it.
You're right not all of them are antibodies, but the ones that aren't might not be working for "other reasons". Yes, that is a cheap way out, but I still think it's worth trying (and I don't generally believe in the amyloid hypothesis)
I'm surprised IgG isn't degraded by insulin-degrading enzyme.
what agencies are more free from politicians manipulating their funding? (this sounds hopeful)
I think DARPA and other agencies trying to imitate them (e.g. Wellcome Leap) are less prone to manipulation and much more fact-driven. Howard Hughes Medical Institute is also good.
As a European, I hate ERC. In some cases, they have not even bothered to discontinue funding principal investigators known to have committed fraud and who had to retract major publications.
Normally there's excitement when the research offers some weird or novel tie in or a better way of doing a thing or solving a problem.
But then again these fields don't have the same structure of paymaster.
This unfortunately isn't the case. There is friction because there is a fork in the road for particle physics. If we build or extend the LHC it is fundamentally a p-p hadron collider collider.
There is significant new evidence of new physics in hadron/lepton interactions and from the neutrino sector. Neutrinos are tricky but we feel we have a handle on these, which is pushing more people to want to build a large clean lepton collider either an e-e or u-u collider. The problem with a purely leptop collider is that it doesn't tell us too much about hadron physics (hence why the lhc differs so much from Tevatron).
The community itself has elected those who are in charge to review the proposals from the people with different ideas to allow us to form a coherent argument to go to funding councils/countries with.
I cannot name any other academic field which has managed to achieve such a level of international self-governence when designing projects on such a scale.
String theory?
besides there's tonnes of theory people I know who work on completely unrelated theory problems and ways of working that predate or have come after the dawn of string-theory, complaining this hasn't panned out into M-thoery is to a point of almost being absurdist
If it turns out to be an infection, their whole career has been a waste. Can they even find something to do, then?
It's like this with tons of biomedical research: chasing authority figures and popular trends. I don't think the people doing it are evil, or are necessarily consciously aware of what they're doing, it's just everyone is incentivized this way. I'm not even sure they "honestly believe in what they're doing" sometimes, I think it's more a sense of "this is our best guess" where "best guess" is defined as "popular". It's like FOMO with this alternative of proposing shots in the dark being the thing that no one talks about because it won't get grant dollars and if if fails, won't result in any credit.
The whole mentality is backwards to me. It's as if space agencies kept sending probes around the earth because we don't know much about what's further out in the solar system. We don't do that because instead we celebrate the information gained about other planets, not whether or not that information conforms to some particular a priori hypothesis of a particular person.
Add in indirect funds dependence and you have a recipe for perpetuating the obvious.
Basically, don't blindly trust science, because science isn't just some imagined ideal of objective research. It is fund raising, reputation, ladder climbing, ego, dogma, etc...
People believe all sorts of idiotic things with utter confidence, then act on those beliefs to the detriment of others.
Many of the worst things to happen in the past few decades happened because of ignorant hubris.
IMHO Its going to take awhile for the human species to evolve out of that.
Derek Lowe: Had Enough, Eh? Come Back and Take What's Coming to You! https://www.science.org/content/blog-post/had-enough-eh
>It is hard to even begin to estimate the amount of time, effort, and money that has been spent on this idea. And this is just the antibodies! There are plenty of other whacks that have been taken at the amyloid hypothesis (secretase enzymes and more), and none of them have ever worked. Keep in mind that there are plenty of preclinical efforts over the past thirty years that never even saw the light of day (I was on some of those myself), and the reason you never heard about any of them is because they didn't work, either. Nothing has worked. Not once. The amyloid hypothesis has been targeted again and again and again from different directions with different drug candidates, and never, ever even once has it shown signs of truly helping Alzheimer's patients. I very much include Biogen's Aduhelm in that assessment. So I ask again: how long are we going to keep doing this?
Some quotes from their letter:
> Taken together, the preponderance of evidence argues that using the diagnosis of ASD in research is fruitless because the diagnosis is an arbitrary unscientific “convenient fiction” that has blocked the discovery of replicable neurobiological variation among individuals with serious neurodevelopmental social impairment.
> More than seventy years of research studying the arbitrary diagnosis of autism has not resulted in any targeted medical treatments. Now is the time to abandon the ASD diagnosis in research.
And, somebody always pops up self-righteously insisting Gold Standard Randomized Controlled Trials prove that none of the medications that millions of people need daily to be able function at all have any effect.
Discontent with the DSM is very widespread, in significant subsections of both research and clinical communities – however, attempts to dethrone it in practice are met with opposition from that other current of professional opinion ("it obviously is far from perfect but we need something and nobody's convinced us there is anything better"), and that other current seems to thus far be winning in the money/power/mindshare stakes.
> The wastebasket diagnosis means that no new medication can be found to have any useful effect, because it only treats a small fraction of patients in a trial, and worsens others.
New pharmacotherapies for depressive disorders do get approved – in 2019, the FDA approved brexanolone for post-partum depression and esketamine for treatment-resistant depression; before that, the FDA approved vortioxetine in 2013. Agometaline was approved in the EU in 2009 and and Australia in 2010, although its manufacturer gave up trying to get it approved by the FDA. And there are further new drugs in various stages of the approval pipeline. Brexanolone is particularly interesting as a drug to treat a rather specific form of depression rather than just "vanilla depression".
No denying it could be better, but depression is a much better situation than autism/ASD – although risperidone and aripiprazole are both approved to treat behavioural issues (irritability and aggression) in children with ASD, neither has any impact on core autistic traits (social cognition, obsessiveness, etc). At least for depressive disorders, we have approved pharmacotherapies to treat their core symptoms, even if they only work for some patients some of the time.
And, risperidone is a terrible choice of treatment. Anxiolytics can be very effective.
It is that the med under test could perfectly treat the small number diagnosed who actually have the illness it addresses, and have nil or negative effect on everybody else given the same diagnosis who have an actually different illness. According to the RCT, it just failed.
Validity of RCT results is limited absolutely by validity of diagnosis. Bad diagnostics, bad results. That doesn't stop people from running invalid RCTs, so it should stop people from citing invalid RCTs.
But it doesn't.
autism probably covers hundreds of discrete genetic disorders that share similar pathology. for instance, Rett syndrome is sometimes considered part of ASD, but only explains a small number of ASD diagnoses.
I don't think that precludes ASD from being a useful diagnostic category, though. behavioral therapists don't need to know your genotype to help you cope with sensory overload. schizophrenia probably works the same way, but you still prescribe antipsychotics regardless.
It is possible to have "sensory overload" – even severe problems with it – yet not have enough of the other symptoms of ASD to meet its diagnostic criteria. How do behavioural therapists treat sensory overload in a person without ASD? Pretty much in the same way that they treat sensory overload in people with ASD! Conversely, it is possible to meet the ASD diagnostic criteria, and yet have no sensory issues needing treatment – such people exist too.
That's the thing – received wisdom justifies the clinical use of diagnoses as useful in treatment planning - but if you subject that received wisdom to scrutiny (too rarely done), it doesn't hold up very well. Almost all treatments in psychology/psychiatry/etc are (at best) symptom-specific not diagnosis-specific – almost all symptoms occur in multiple diagnoses, and many diagnoses have no one essential symptom. If person A has diagnosis B with symptom C – their treatment for symptom C will often be very similar, even identical, to the treatment of that same symptom in some other person who has completely different diagnoses instead.
> schizophrenia probably works the same way, but you still prescribe antipsychotics regardless
The same point applies to medications – medications don't really treat disorders, they treat symptoms. Antipsychotics are used to treat psychosis – which is a symptom which occurs not only in schizophrenia spectrum disorders, but very commonly seen in mood disorders as well (bipolar disorder with psychotic features, depressive psychosis), and (less commonly) can occur as a symptom of many more. Yet, whatever their diagnosis may be, a person with psychotic symptoms is highly likely to be prescribed an antipsychotic.
Added to that, you can also be prescribed an antipsychotic without having any psychotic symptoms, since various antipsychotics are FDA-approved for treating non-psychotic conditions, including anxiety, behavioural issues in children with autism/ASD, bipolar disorder, depression and Tourette's syndrome, along with various non-specific symptoms such as "agitation", "behavioural problems" (ADHD, ODD, DMDD, conduct disorder, personality disorders), and "hyperactivity" [0] – to say nothing of their very widespread off-label use.
With regard to evidence, the article mentions APP gene variant causes early onset AD; but there is another variant in the APOE gene that is the strongest genetic risk factor in late-onset AD. This gene too is in the Abeta buildup pathway.
With that said, I think that NIH study sections allocating AD research funding should not give preference to a particular molecule or theory. If the Abeta hypothesis is indeed the most compelling, grants focused on Abeta topics should naturally be stronger. They shouldn't need any additional bias to stand out.
Iirc there's something about lipid raft homeostasis being out of whack leading to increased likelihood of amyloid nucleation, but our ability to measure lipid rafts in vivo is even weaker.
(1) Pathological levels of amyloid-beta and tau are present in cognitively normal individuals.
(2) Some individuals clinically diagnosed with AD do not have amyloid-beta pathology
(3) spatial appearance, progression and absolute amount of amyloid plaques does not correlate with declining cognition more conclusively than other pathologies.
(4) It's not even clear that that amyloid-beta pathology is the first AD biomarker. Not even among those with APP, PSEN1 and PSEN2 biomarkers.
(5) it looks like autosomal dominant AD may be a different disease than sporadic AD and results there don't apply.
(2) Amyloid plaques are not the only thing that causes dementia. However genuine AD diagnoses are confirmed post mortem via autopsy and are typically assigned a BRAAK score (most large scale studies require plaque confirmation for cohort inclusion; i.e. AD definitionally requires amyloid presence).
(3) From the large datasets I've worked with, BRAAK score and AD age of onset are HIGHLY correlated. I'm genuinely curious to hear what biomarkers are more correlated.
(4) What is clear-er?
(5) Agree LOAD and EOAD are not identical diseases.
Guidelines and diagnostic criteria based on amyloid-hypthotiesis is not good reference point if we question amyloid-hypthotiesis.
>I'm genuinely curious to hear what biomarkers are more correlated.
>original neuropathological guidelines for AD were built on the correlation of amyloid plaques and NFT counts to cognition, much research since has established amyloid plaques are less well correlated to the clinical and anatomical progression of AD than other pathologies, including synapse loss [266] and NFTs [184, 197]. ... evidence since has indicated neuritic plaques correlate to declining cognition better than do diffuse plaques [188], indicating that even if NFTs correlate better, plaques counts are still useful determinants of dementia severity. https://link.springer.com/article/10.1007/s00401-018-1918-8
>(4) What is clear-er?
There is evidence that appearance of NFTs, clusterin (protein) or vascular dysregulation. The problem is that procedures and hypotheses for disease progression are based on amyloid-hypthotiesis, so there is not enough work made to find earlier biomarkers.
"synapse loss" is a better correlate for dementia because, obviously. But synapse loss is the outcome of the disease, not the cause of the disease.
In clinical trials patients who show the biggest decrease in brain amyloid or tau are not correlated at all with any particular clinical improvement (small as they are).
In mice you can prevent amyloids but don't prevent the disease.
From one or two??
Cognitive outcomes of anti-amyloid-β monoclonal antibodies in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...
Had Enough, Eh? Come Back and Take What's Coming to You! https://www.science.org/content/blog-post/had-enough-eh
So there's a small benefit to using antibody treatment. To me suggests that Abeta is a good target, but antibodies are not a sufficient Rx.
Have you seen a brain at BRAAK stage 4-6?
However, if another outcome of that interaction were found, then the "amyloid cascade hypothesis" would be easier to reject.
Recent work by several independent groups has focused on disruptions to the endolysosomal system as an alternative causative mechanism, e.g. Lee et al, 2022, discussed in the link below. One should note that despite the claim in the title, the authors may actually finger APP-C99 as causative in the original paper, which I have read very carefully (or rather fail to distinguish between Abeta and APP-C99).
https://www.alzforum.org/news/research-news/behold-panthos-t...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919248/
A larger trial (n=130) is expected to complete by December 2023 (it was originally expected to complete around now, but just finished recruiting):
https://beta.clinicaltrials.gov/study/NCT03282916?patient=NC...
Got my Tdap, too, because a colossal US Veterans Administration study showed that a recent Tdap booster predicted a 40% reduction in dementia risk. Dunno anything else with that predictive power.
Anyway, does acyclovir still work, anywhere?
For a field with no real results to have "superstars" is a sign of corruption.
Question for those who know: is this a problem in general with the culture of academic science?
I am not a scientist, but I feel like I've seen this story more than once in science-enthusiast media: an established but incorrect idea cannot be challenged because it is a risky career move and hard to get funding for.
I understand that crackpots exist, but I wonder how much of this culture is really a barrier to keep out the unsubstantiated and how much of it is just protecting turf and sunk costs?
I have tons of confidence in the scientific method, but decreasing confidence in the institutions that practice it.
Recently, the Younger Dryas Impact Hypothesis, finally firmly established in 2018, was fought tooth and nail for a decade, with numerous shamefully disingenuous papers published (e.g. insisting melt-glass grains were pollen). The de-facto curator of the Wikipedia page, a retired historian with no geology background, did and still to this day does his part to throw up doubt.
It's a trouble with most grant driven activities. If I control the money then people that don't advance my beliefs aren't getting funded. Those whose competing ideas that prove me wrong will be curbstomped. The true amazing grantees fund the competition too.
I suppose capitalism has fueled it to one extent or another. Depending on your outlook, that could be a good thing or a bad thing.
In our defense, at least we're not burning people at the stake for it anymore.
Its definitely not new, there was such a Cabal for ME/CFS research for nearly 60 years that considered the disease depression and to treat it with exercise and CBT, they successfully sucked up all the funding (still do) and have published numerous big studies including completely fabricated data and they still keep getting all the funding.
MS was similarly led down the wrong path for 2 decades with a similar cabal and limited funding with most research rejected and it only got exposed when the US Army noted that only those that caught EBV (mono,glandular fever) went on to develop the condition. Remains to be seen if the research money is no redirected due to this research and the enormous media coverage.
It is by and large the normal when it comes to disease funding, cabals with real promising research even drugs that showed promise in small trials or diagnostics that appear to work well getting rejected for funding for nonsense reasons. Its not a uniquely US/NIH issue either its definitely present in the UK's NHS as well.
Alzheimer's research having a focus on amyloid plaques makes perfect sense in light of so much data implicating it as a mediator of the disease. It's hard to say, even in retrospect, whether this focus was warranted or not. Allocation of scarce resources is hard, and everything comes at the expense of something else. It's easy to pick out 'fringe' ideas that bore fruit and lament how hard it was for them to gain traction. But what about all those that didn't? Were we really balanced too strongly to dominant ideas, or is science simply difficult?
You simply can't address this issue with the recent success of new or fringe ideas. You'd have to do something like systematically look at proposal acceptance rate vs. some subjective measure of heterodoxy vs. ultimate success. I just don't see compelling results from something like that.
If you have a hypothesis of the cause of a disease, and you create drugs that effectively treat it, and those drugs don’t effect the disease symptoms or progression you need to accept the hypothesis is wrong.
We don't know.
Seems like low lying fruit that someone would have looked into.
I regularly take zinc and iron supplements and have used aluminum based deodorant, so I hope there's no relationship!
I think in some cases it actually made the symptoms worse.
I picture it as a clog in a pipe. The clog is large and strong enough to break the wall of the pipe. You can remove the clog, but you've still got a break in the pipe that was not repaired.
Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress toward a cure (2019) - https://news.ycombinator.com/item?id=31828509 - June 2022 (307 comments)
How an Alzheimer’s ‘cabal’ thwarted progress toward a cure - https://news.ycombinator.com/item?id=21911225 - Dec 2019 (382 comments)
The amyloid hypothesis on trial - https://news.ycombinator.com/item?id=17618027 - July 2018 (43 comments)
Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017) - https://news.ycombinator.com/item?id=17444214 - July 2018 (109 comments)
I applaud the researchers who have spoke out against the consensus at their own professional risk, it's a shame they have to take on such burden.
(many careers were ended. In some cases, states threatened to pull licenses or even imprison researchers for even considering alternatives)
Where?
Washington, Michigan, Minnesota, Illinois, New York, New Jersey, and Arizona all threatened to do so, though I have been unable to determine whether any licenses were actually pulled.
California threatened criminal charges, though I have no evidence that any were ever actually filed.
People who acted in bad faith on data that was demonstrably bad were rightly defenestrated by the medical and scientific community. However many of those same people found themselves right at home in a new cheer squad of people who are more than happy to invest in beliefs over data. The mop up on the shitty evidence is drawing to a conclusion, with events such as the recent NEJM publishing of the ivermectin study. But stupid knows no bounds and the scientific method is going to be mopping up the damage from this one for a long time
It just turned out not to work. I don't know of any evidence that trying it, when we had literally nothing else, did anybody any harm. All the harm came from people using it instead of, later, doing the things that did turn out to actually work. Probably a few people even cleared up a chronic worm infection they didn't know about.
What I did not see, and expected to see, was a study of relative infection rates in people already on ivermectin for an on-label use vs. people who were not. These came out pretty early vis a vis chloroquines, showing that people who had been taking that got COVID-19 just like anybody else. Maybe periodic ivermectin doses wasn't a thing...
This becomes more and more rare as the science becomes politicized, as we saw with COVID-19. Recommending against masks early, then justifying it post-hoc with the noble lie theory, over-promising what vaccines could do, lack of research into air filtration/sterilization, etc. Speaking out against these became a very difficult thing to do for someone in power with a lot to lose.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C33&q=air...
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C33&q=mas...
The Scholar results do not support your claim.
The very core of science is the idea that a theory is correct because it can stand up to extreme scrutiny.
When I did my graduate degree that idea was drilled into us. It’s your job as a scientist to try and tear apart what other scientists say.
If they can defend their conclusions under such questioning then that advanced the science. If they can't, then it's not a very good conclusion.
In general, where a set of ideas are protected, despite contrary, high-quality, evidence, this is the opposite of 'trusting the science'.
In that phrase, "the science" refers to the enforced narrative.
And as seen here, sometimes scientists don't actually follow the scientific method, they fall trap to entrenched interests and other biases.
The people that tell you "trust the science" are not usually suggesting you get a PhD and study this yourself. They are actually suggesting you trust the scientists - which may or may not be good advice based on the field (e.g. trusting physicists, climate scientists, virologists: good; trusting dieticians, Alzheimer's researchers: possibly bad).
You mean like religion?
you shouldn't "trust the science" when a single paper makes extraordinary claims and that haven't been replicated (e.g. the original vaccines-cause-autism paper itself, which seems to have been outright fraud.)
you also shouldn't trust the science beyond what the study can show. I trust that amyloid shows up in Alzheimer's brains, that neurofibrillary tangles disrupt neuronal function, that APP mutations lead to early-onset Alzheimer's. but beyond that, the science is only suggestive, not conclusive.
no experiment has proven the amyloid hypothesis, only pieces of the patchwork. smart, reasonable people can disagree on how those pieces fit together. all while trusting the same science.
Dogmas are everywhere, not merely within religion.
In science it’s merely framed as «paradigms».
This story details how it looks.
Current article notwithstanding, of course…
But the whole "at least spinkle some [latest trending buzzword] in your proposal otherwise you won't get published/funding", is absolutely 100% true.
Anecdotally, I wrote a paper a few years back, which solved a problem with fuzzy methods. Fuzzy methods are considered "obsolete and superseded by Bayesian methods" by many, which mathematically is borderline retarded, since fuzzy measure theory is in fact a superset of probability theory. My then supervisor urged me to include a whole paragraph on how "these methods we're proposing are some new kind of fuzzy that draws from bayesian mindsets and any relationship with traditional fuzzy methods is purely coincidental for lack of a better name bla bla bla ..."
That's nice. No one thinks they're doing evil.
>A frequent reason top journals declined to publish her papers, as they did those of other amyloid skeptics, was previous rejections. As one peer reviewer wrote about a funding proposal Itzhaki submitted in 2010, “very few [of your] papers have appeared in the most highly regarded journals.”
I don't think "cabal" is too harsh a word to use here. "Other journals have rejected you, so we will, too."
> One of the four reviewers gave her scores of “poor” (3 on a 10-point scale) on key criteria, arguing that because “there is no conclusive evidence for a major role of this pathogen in Alzheimer’s disease,” the research “will not have an impact on advancing the field of dementia research.” A second reviewer called the role of pathogens in Alzheimer’s “a fringe topic.” Although one gave Itzhaki scores of 10 (“outstanding”), the two dismissive reviews sank her chances.
If the amyloid hypothesis had made stunning progress, that approach might have made sense. If not... "the jury is still out, so let's hear your ideas" would be the real Science.
It's always harder to convince them than when they already agree, but at least it's not impossible.
I'll pick up on the thread of "telling people to get better sleep" is insufficient.
Amyloid plaques are cleared through the glymphatic system, and the clearing coincides with slow-wave oscillations (SWOs). It is believed that the SWOs trigger the clearing, and this is a current area of research with a group we are connected to.
Your sleep naturally degrades as you age, and, in particular, we get less of these very important SWOs. Auditory stimulation has been proven to increase the power of SWOs and there is lots of research on the related cognitive improvements seen after just one night of stimulation. There are also hormonal responses related to the immune system, and many other benefits.
A cure for Alzheimer's is important, but improving the neurological function of sleep, what we call Sleep Performance, is more important. It's like the difference between telling somebody to eat a good diet, or get more exercise rather than coming up with a pill they can take when they are already obese.
If you want to find out more about the science behind the SoundMind DeepWave stimulation, check out https://soundmind.co/research - there are more papers I will be adding to that page shortly.
The issue is that politicians have for decades described this sort of research as "government waste".
My sense is that politicians don't really understand much of the problems affecting research. They hear researchers complain about NIH funding obvious studies, and don't realize that what the researchers mean is "obvious to an expert in any remotely related area", not "obvious to a person with no understanding of the subject matter." Then they pull in experts, and end up with hyper-credentialed persons who have benefited from the very process that needs reform.
It's sort of a vicious circle.
https://pubmed.ncbi.nlm.nih.gov/32467879/
https://pubmed.ncbi.nlm.nih.gov/32959702/
also, sleep deprivation increases the alzheimer's protein:
https://www.nih.gov/news-events/nih-research-matters/sleep-d...
Say somebody wants to get funding to fight AIDS, based on the hypothesis that it is caused by something else than a virus. The research community would oppose funding this and they would be right. At some point you have to reject some hypotheses, there's just not enough time and researchers to keep researching every not-so-promising hypothesis.
Sometimes the research community will get that wrong but this is the cost of having research focused on the most promising hypotheses.
As soon as we get good data as to the cause, I think we'll be able to eliminate it pretty quickly. For example if we find that it is spread by contaminated milk, we will make tests for the disease on milk and soon get rid of it.
I'm not convinced that everything has a cause that can be prevented.
To some extent these exist, like HHMI. This article does not go into detail about why those institutions did not fund different research, which would be interesting to explore.
Consideration 1: Amyloid itself is a structural characterization of protein assemblies. Amyloid structures generally form in intrinsically disordered (ie unfolded under normal conditions) proteins as a low-energy conformation that is self-templating and derives its stability from a large number of interactions between many copies of the same protein. Amyloid is not really related to protein function in a direct way. The biological roles of disease-associated amyloid-prone proteins (some famous ones are Aβ, Tau, and TDP-43) can be quite varied in the non-amyloid state. These proteins are also associated with neurodegenerative disease through orthogonal means, namely through genetic analysis of disease-related mutations, so it isn't just the fact that these protiens wind up in amyloid fibers that leads us to believe that they're associated with neurodegenerative disease. So, we know because of genetic analysis that these proteins are associated with disease, they can all form amyloid, but we aren't losing any consistent biological function due to their dysregulation–this strongly suggests that the amyloid or otherwise dysregualted state of these proteins is problematic on its own.
Consideration 2: Recent structural work has tied different amyloid isoforms to different disease pathologies. I work in an adjacent field to this and these results were really what changed my mind about the validity of the amyloid hypothesis despite years of doubting/discounting it (often in a public way, often to the detriment of my own career–turning the corner on this was a bit challenging). See this paper and the first 5 citations in it (https://www.nature.com/articles/s41586-021-03911-7) for a good example of direct structural links between amyloid structure and disease pathology, and the associated comment (https://www.nature.com/articles/d41586-021-02611-6) for a good overview.
Consideration 3: The presence of amyloid plaques in patients in the real world is generally assessed by histological analysis or other methods that don't capture information at the molecular level. This, combined with the two points above that seem to point to some shared structural features of amyloid-prone proteins being disease causative, suggests to me that studying amyloid (or maybe more specifically the behavior of amyloid-prone proteins) is still a worthwhile endeavor.
Less than a week ago ANOTHER amyloid hypothesis drug failed a Phase III, this from Roche. There are at least three more drugs based on that in Phase III right now (Gantenerumab, Donanemab and Lecanemab). So the drugs that are getting to Phase III are still based on the amyloid hypothesis. Now note that drugs in Phase III are a lagging indicator, so the initial screening and phase 0 research might have changed direction, but the part of the iceberg sticking up out of the water is definitely still amyloid based.
There are more stories like this that will come out eventually over time. Unfortunately you're branded another Alex Jones for saying this out loud.
Once you see how corrupt and political something as non-partisan as Alzheimer's research is, you realize how terribly corrupt and purely narrative-controlled "the science" is for partisan topics.
What they found was that having had a Tdap vaccination booster recently predicted a 40% reduction in dementia risk.
They then replicated the result with a wholly disjoint population treated in a different system.
40% effect is better than aspirin for headaches. A confounding factor with that much correlation would be almost equally interesting even without causative effect. I don't know of anything else that predicts dementia risk.
They had no idea which component of the Tdap vaccine might be responsible. But you can bet I went out and got my Tdap booster right away. Because why not?
You see these sorts of things a lot in health studies. For example, someone that goes to church often is more likely to live longer. Yet, if you look at what's happening, someone that isn't going to church is more likely doing that because they can't (IE, they are bed ridden) which in and of itself is a strong predictor for whether or not you are going to die soon.
Disentangling these sorts of cause and effects seems like something medical journalism does poorly.
Consider String Theory.
The article points out the trial was stopped because the drug did not work. The only thing that changed is that the FDA approved it anyway. All available evidence still suggests that it doesn’t work.
https://www.reuters.com/business/healthcare-pharmaceuticals/...
Keep in mind that, while only one patient was known to have died at the time the article was written, not a whole lot of patients had been treated.
This article links Aspartame to some wild problems. One of them is Alzheimer's.
In the early 2000s i worked for a pharma company. A woman named Beryl told me they knew aspartame caused Alzheimer's if it went over a certain temperature.
If it was anything obvious in the environment, I'd hope we'd know by now...but it may be something hard to measure in large epidemiological studies like a more rare pollutant or something we overlooked in creating large observational datasets?
Anyway, I'd encourage you to link the best studies you've found and that may help some to read them.
Basically, if you’re going to make a claim and not be some armchair scientist, you need to not Dunning-Krueger yourself. I’m not saying you have, but the way you’re representing yourself suggests you’re at risk of it