This stifling of competing ideas, say a growing number of scholars, is a big reason why there is no treatment for Alzheimer’s. (The four approved drugs have no effect on the disease, providing only a temporary memory boost.)
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.
> Helping people get a good night's sleep -- without drugs -- would likely help, if only to stave it off in those at risk.
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.
I think the argument here is that recent research indicates that a chronic lack of sleep can cause Alzheimer’s, and I don’t think most people realize that. Beyond that, telling people to try to get more sleep is not really medicine. It’s not really specific or actionable, and it doesn’t help people with understanding how to get more and better sleep.
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...
>recent research indicates that a chronic lack of sleep can cause Alzheimer’s
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.
While you may be right (FFI fatal familial insomnia, not foreign function interface) is an amyloid disease and the amyloid seems to cause insomnia, not vice versa -- there are some real proposed mechanisms suggesting that lack of sleep prevents clearance of junk in the brain, that then cause the cell death associated with Alzheimer's.
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.
You're basically just reinforcing parents comment (correlation does not imply causation) because those studies mention the same problem with their design thus they can't come to a valid conclusion.
The arrow of time really does help an inference of causation. However with Alzheimer's patients we're not generally taking brain biopsies of old people to surveil for Alzheimer's plaques, so we don't have the arrow of time in either direction.
A valid conclusion can come from studies for which, in this case, there was no funding because of poor rhetoric like this. Correllations which merely suggest causation are indeed sufficient as the focus of hypotheses.
Scientists too often forget that a hypothesis is a valid part of the scientific process, and the aversion to adoption of one without an attempt to gather further data about it is shoddy, unprofessional, and more reminiscent of dogmatic orthodoxy than of science.
The next time you think to say "correllation does not imply causation", maybe think to ask if anything more can or should be learned about either the correllation or the cause being investigated, and consider that such obstruction of efforts to collect more evidence is precisely why the present data is inconclusive.
The fact here, from TFA, is that there was no such problem with the studies' design, but rather with the myopic cognition of those who obstructed them.
>The next time you think to say "correllation does not imply causation"
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?
> 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.
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.
Genuine question. How is sleep tracker information actionable?
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?
If you know what times you normally enter Deep/REM sleep, you know what times it's important to get to sleep by and to not be disturbed at those points in the night. They certainly vary by person and environment, but night to night they are fairly stable. Also, a lot of people are in denial about their sleep issues, "I don't hear any snoring".
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.
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!
More often then not, they tell you 'inconclusive' results unless you are observed snoring and waking or having some sort of sleep obstruction. And then you get to pay a $3-4k bill for the worst night of sleep of your life, if you were in the States.
I really have the least amount of respect for sleep clinics I have had the displeasure of working with.
Outside the U.S., I paid exactly nothing for a night in a sleep clinic. I had the option of a take home kit, but I happen to live within walking distance of the hospital where the clinic was located, so I chose to sleep there.
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.
Yeah, I mean I would definitely recommend going to a hospital in Thailand for the sleep study rather than UCSF's sleep clinic. You might even save money with the cost of room, board, and plane tickets included.
The problem is that we don't understand most sleep disorders.
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.
$3-4k sounds steep? I guess that is where they provide the accommodation. I had a take home one and it was much cheaper (privately paid IIRC, not subsidized by government). Outside of the US.
They provide the accommodation and then have like 10 people being monitored by 1-2 technicians overnight. It is pretty lame to be billed the amount they did for the equivalent of a couple hundred dollars of overhead and then manhours.
>> Helping people get a good night's sleep -- without drugs -- would likely help, if only to stave it off in those at risk.
> 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.
Whoever agrees with the philosophical idea of “Sin taxes” deserves whatever fascist world they end up creating. The idea that I owe someone because I decide to indulge in something unhealthy for me implies that other people own me.
In an unregulated system there are strong "sin incentives" created by (some) market forces. In a way people are manipulated to become passive couch potatoes craving trash food and sugary drinks, staying awake to binge watch some netflix series. It seems fair that governments take some corrective measures.
So it would seem you are suggesting we have no free will/agency? If so you cannot take credit for any achievement you accomplish or lay blame on anyone for anything no matter the deed because we would be nothing but products of our environments
so-called "sin taxes" are morally neutral but economically efficient. Explanation: one of the problems with taxation is that taxes distort the economy by changing prices which change consumption; "sin goods" have inelastic demand functions--smokers still want their cigarettes--so taxation doesn't change consumption, which lessens side effects of the taxation, for example not increasing unemployment of cigarette workers.
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.
I suppose the logical question is what defines justification for any tax on anything; if this can be defined perhaps we can establish reasoning for what items should be taxed and not be taxed.
The idea that you "decide" to indulge in something unhealthy for you, and it was a free decision and companies had nothing to do with it, is a complete joke. We know humans are biased, we know we evolved to like fats more than salad and sugar more than water, we know advertisers influence us, we know companies spend tens of thousands of people's work and billions on advertising and that vastly outpowers a single person's ability to "choose freely", we know companies wilfully mislead and take advantage of our social nature (look at that respectable admirable sports star associated with our product! Look at the work of Edward Bernays and 'Torches for Freedom' getting women to start smoking cigarettes by associating them with the women's liberation movements) and take advantage of our judgement of colour and contrast and intensity (the same product in a cheap box looks less desirable than it in a bright stylish box - and both product, box and brands might be the same company behind the scenes), and our human decision fatigue and temptation for convenience by putting sweets near checkouts. We know companies specifically target children for their suggestibility with methods like adding toys to cereal boxes, advertising during Saturday morning cartoons or loot boxes in games. We know companies lobby for regulations which help them or hurt their competitors. We know society is organised so the big get bigger - McDonalds can outspend a startup Salad bar by millions to one. We know companies pay scientists to lie about the safety and efficacy of their products, and to hide results that say the opposite.
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 you implying that we have no free will and that we lack the agency required for responsibility of our action? Dangerous doctrine there if so; it would imply that all criminals no matter how heinous the crime are victims of the system and thus cannot be punished without said punishment being just an emotional expression of vengeance. It would also mean that you could never take credit for anything you have done because it is just a reaction to your environment. These are only a few implications of a lack of free will/agency
I'm implying that people who dismiss the effects of the environment (advertising) on them by saying they Ayn Randian free-will themselves above it all, are either deluded or malicious. And that instead of systems which are openly hostile to humans which everyone must constantly burn free-will to defend against, we're a lot better acknowledging the predatory nature of advertising, and the limits and fallibility and weakpoints of free will, and en-masse building pro-people systems instead of pro-profit systems.
We are social animals. You derive a lot of benefits from living in society, it has a price.
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.
Isn't this a natural aspect of any system of government run "universal" healthcare?
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.
No, because most states with a state-run healthcare system simply recognize that health is a basic human right. It's not about incentives, or efficiency, it is about basic human decency.
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.
As a counter example, look at how many countries have state funded healthcare with restricting unhealthy food or behaviour. By my count 66 countries have state funded health care and 0 have restrictions on unhealthy food or behaviour, (I admit my count was limited)
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
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.
So in the 66 countries you're referencing, none have restrictions on alcohol or tobacco? No warning labels, taxes or restrictions on sale?
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
It can occur in free, capitalist societies too. And not in the sense that they "restrict" like an omnipotent government, instead they discourage what is bad and promote what is good. E.g. we have private medical health care here in SA and one of the biggest providers offers all sorts of free goodies and incentives and discounts. They literally partner with stores to get you discounts and points on healthy food choices. Now, I know they also use this data for other purposes but they also happen to help the health of the market. If we can keep it up without having the profit motive distort the benefits too much then its a win win.
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
Are doctors not already telling people to eat healthy & exercise?
> 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.
Even in the presence of healthier lifestyles, the human body would still accumulate problems as part of the normal aging process. It's not like Alzheimer's would just go away if people started going on more walks and ate more vegetables. It's not an "emerging disease".
Maybe part of the problem is that we consider these things ”sins”, with all the subconscious burden of suffering for all eternity in a fiery pit thanks to a belevolent god who made that place, and who also loves you.
Maybe there should be? There’s got to be a startup there. Combine long term health insurance with a research arm that ensures the disease is cured and it never needs to pay out?
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.
Single payer health care seems to be another reasonable way of aligning incentives, although as it’s critics will point out it also has other drawbacks.
There is plenty of money in preventative care. You should check vaccine sales numbers. A vaccine platform just got acquired by a drug company for over $3B.
Wellness - dieticians, massage therapists, smart watches, etc - is a multibillion possibly even a trillion dollar industry.
There is a ton of money in preventative care. But even if you were right, we have no idea if prevention of Alzheimer's is even possible, or what it would take to do so.
I hear the exact same hot takes wheb diacussing life extension. 'eat healtheir', exercise more' etc...
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.
Diet, exercise, and good sleep are exactly the kinds of things that make people less frail at 90 (or 60 or 50). If you’ve ever met someone who isn’t frail when they are older it’s because they stayed active throughout their life. This doesn’t necessarily mean exercise, but it could mean doing lots of yard work, going on walks, etc.
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.
> Diet, exercise, and good sleep are exactly the kinds of things that make people less frail at 90 (or 60 or 50).
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.
I once looked at conditional lifespan data given that one reached a particular age. What was interesting that for India and Mongolia, countries with very different cultures, lifestyle, diet and climate, after 75 years the remaining lifespan was the same.
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.
Increasing levels of dementia are likely being observed because we have healthier older people than ever before. Anecdotally I’ve known 3 people with severe Alzheimer’s who were extraordinarily robust - healthy in every other way into their eighties. In a earlier era they likely would have been dead before their dementia became incapacitating.
Drugs that can't be commercially monetized can't get through the rigorous and extremely expensive approval process that allows your doctor to write you a script for something you can fill at the pharmacy.
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.
Thats not true. Many conditions are well adressed by informing and training those at risk how to best take care of themselves. Current medicide really fails at this. In fact it fails in many arreas where a longterm and consistent influence is required.
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.
> Many conditions are well adressed by informing and training those at risk how to best take care of themselves.
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.
> Or maybe the real problem is the excess emphasis on finding a drug in specific that can be commercially monetized
> ...
> 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.
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.
Do we need medication to cure or at least treat the disease? Hell yes!
But preventing people from getting the disease in the first place is also very important.
> 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
I don't know. I do know for a fact that sleep is when the brain "takes out the trash" and lack of sleep leads to accumulation of stuff that shouldn't be there.
> 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.
My experience is that many prominent professors behave in a monopolistic way. That is, they try to sabotage theses, grant applications and publications in review that go against their own research.
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.
I was lucky enough to witness the sea change in a relatively intellectually honest amyloid lab in the 2003-2009 regime. We were actively pursuing results in the amyloid hypothesis but just about every other lab meeting we were careful to mention that the hypothesis might be wrong. All of our papers say "suspected"... Around the end of that period we were getting word that the first attempt at a drug targeting amyloids was failing, and it was a common morbid joke among all of us that this was all a red herring.
~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.
I don't honestly think that anyone has been put at misery. At best we will have taken slightly longer for a cure (or maybe we'll never find one). I feel like there area few too many ethical gymnastics you have to do to blame overzealous scientists for chasing down the wrong rabbit hole. But, yes the trait in general of blinded belief (versus belief used to drive effort and focus but with self-awareness that it's just a tool) among some scientists feels uncouth. I am lucky to not have had to deal with that personally. I did see it in some neighboring labs, some of those grad students got utterly fucked and when they presented consolation thesis defenses for seven years of misery, they had the dazed look like someone who had just escaped an underground cult to see the sunlight finally.
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.
These are the kinds of replies that still make HN one of the best comment sections on the internet, if looking at peaks. (The average is not great, but there's huge variance.)
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.
My comment was extremely flippant. Let me provide an example to explain my point of view.
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.
As you pointed out in your original comment, VC's will def fund moonshots and big growth ideas with 1 in 10 or 1 in 100 chances for payoff. These don't make short term profits, but they have the potential to do something dominating.
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.
What would “more foundational research on cures” look like? I do cancer research and, frankly, the work feels pretty foundational. I’m curious what you would change.
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.
>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?
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.
Hypothetically, yes. Practically, that almost never happens. The reason the treatment costs $50k/month is because there is no alternative, and that's how much insurance will pay for it.
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.
I work in pharma. Pricing in pharma for drugs like that is complicated. Usually these drugs do actually require rather expensive manufacturing processes, that have to run in extremely large facilities with extensive QA, but in fairly small batches.
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.
Many drugs invented by US companies are available cheaper in countries that don't respect US IP law (with no differences in quality/QA process/etc). The reason for this is obvious: in the US the government gives the inventor a temporary monopoly.
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.
This is nonsense. Most Western nations fully respect IPR and patents.
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.
The price of drugs in US also reflects expensive R&D and sometimes even more expensive approval process. Plus the companies has to account for the possibility of third parties manufacturing without the license which in turn requires higher unit price.
I am not aware of any large-scale alternative manufacturing facilities that explicitly avoid IP laws and market their product legally. Can you give an example?
I work for a US biotech that is wholly owned by a EU pharma, not the US.
It's the scandals on stuff like Albendazole that make y'all evil, not the cancer drugs. I mean the FDA forces us to live like we are in some Soviet style dystopia. Some ancient commodity antiparasite drugs that are cheap as salt -- so abundant that people literally use them as a drench on livestock -- can only be bought from one or two approved marketers (manufacturers), through only approved distribution channels, only at approved retailers, after unnecessary high-skilled laborers press some buttons, and only after you have the right script from the right gatekeepers.
Ok, so here's a thought: who makes money if people don't die of cancer? Let's assume they're all retirees. Agriculture, housing, the local taxation authority, and possibly their immediate kin (assuming, on average, people love their parents and want to spend time with them).
Maybe Monsanto, Toll Brothers, and local governments should be funding cancer research?
I think this is being seen in particle physics right now, with CERN campaigning to fund a successor to the LHC that other particle physicists believe has little chance of finding anything new.
I can't name of a global bio experiment looking for international funding to build a massive project.
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.
hurhurhur big think... string theory has at the very least given useful tools for particle and field theory as a research area, saying this doesn't work is like complaining that I can't take home a jar of magnons to show someone
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
It was an order of magnitude more difficult to raise VC money for biotech back then.
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.
I have to ask, do you have experience in this area? Because it doesn't agree with my limited experience and I'm curious when/where you were involved with biotech startups and funding in the 90s/early 00s.
I'm an outsider, but to quote credible external sources, Science AAAS writer Derek Lowe documented that the biotech startup scene was large and relatively easier to get investments in from 1991 to 1994, with stagnation in 2012 [0].
McKinsey separately reported that there has since been another boom in the biotech sector in the 2020s [1].
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.
I was in grad school at that time, in a program that heavily emphasized bio-entrepneurship. It was not easy to get money to start a biotech company at the time. The only ones I can recall required a star professor, a working technology, a university patent, and even then, most of them failed or pivoted.
I was referring to academic politics. That is, professors steering funding to their niches and trying to dry out alternative ideas.
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.
Probably unrelated, but I've realized from dealing with certain people in the criminal justice system, that almost nobody believes they are evil or doing bad things. They just want to do what they think is right, believe that what they are doing is common and acceptable, think often justice takes strange forms, or otherwise can justify what they do till the day they die. The worse someone is, the more strongly they can justify what they do.
Do you think Adolf Eichmann saw himself as evil? I do not. He was “following orders” and thereby being good soldier. I would bet Hitler and Stalin also believed themselves to be good people. Same for most all dictators and mass murderers.
I think it's a mistake to believe they all believed in good and evil in the first place. I don't. Those ideas exist for the purpose of domination. Social life, in that respect, is actually just conflict. Attempting to make ones will seem objective are what concepts like "good" and "evil" are for. Ethics should rather be focused on what we all want and equitable conflict resolution. Anyway, I think a lot of those people just reject the concepts as well, but probably for less enlightened reasons.
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.
> Things like the Golden Rule, for example, can be deduced logically to generally be in all of our interests.
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”.
> 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?
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?
I'm not a philosopher or a Nietzsche expert, but Nietzsche wrote about this at length in his book "Beyond Good and Evil." It's been a while since I read the book (surface-level Wikipedia summary link: https://en.wikipedia.org/wiki/Beyond_Good_and_Evil), but the argument he advanced was to frame morality as a means of people who lack power to feel superior over people who do have power.
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).
> 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.
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.
They weren't meant to be. I presented Nietzsche's views as evidence that there is significant writing against objective concepts of good and evil, then provided counter-arguments to his views.
If I’m stronger and have more guns, why wouldn’t I want that system? Then I could kidnap, steal, etc. become wealthy through theft and spread my genes through rape. Isn’t this what we had a few tens of thousands of years ago?
Agreed. I don't think anyone can truly see themselves as evil. I think it would go against our very nature of self-preservation.
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 assume you're familiar, but a whole book was written about the various forms of evil perpetuated by the Nazi leadership. Eichmann isn't a good example- he knew he wasn't just following orders. The example you're thinking of is probably https://en.wikipedia.org/wiki/Wilhelm_Keitel who apparently wasn't even smart enough to realize the magnitude of what he was doing.
That's why the real diversity - the diversity of ideas - is important. There aren't many mustache-twirling villains that wake up with the thought of suppressing ideas for the fun of it. Most people who suppress ideas think that's because they have the right ideas and the others have wrong ideas. Except turns out even very very smart people can be mistaken from time to time. And maybe it's worth to allow some ideas that we think are wrong to be around - just in case some of them turn out to be correct later.
I think this is the most important take away, with lots of nexus into other medical and non-medical science. Cognitive bias is a real tricky beast and even the best are not immune. Strategies to celebrate and learn from failure, and to allow for alternative and moonshot ideas to be tested should help.
I agree, but as many already have commented, I think believing "I'm wrong and someone else is right" goes against self-preservation for most. I have been working for years on my own mental-emotional health and I still get caught into patterns of destructive ego. I think this is mostly an evolution problem. Our minds are built, layer by layer over time to incorporate certain patterns of thinking that helps perpetuate our species. But now with our current technological achievements, the mammal part of our brain is an actual detriment to human progress, at least to a certain extent. Until we evolve past those part of our brain that have a hand in creating these blind spots, I'm guessing we are going to be subjected to the problems like cognitive bias for a long while, at least a couple of more generations.
You don't need to go as far as "I'm wrong and someone else is right". It's enough if you admit that "while I am sure I am right, many smart people before claimed that, and some of them turned out to be wrong. Knowing that, I will sacrifice some of the perceived efficiency and agree to admit the chance I might be wrong, and so allocate costs and effort to be spent on the case when I'm wrong, even if I am currently convinced that these costs and effort will be wasted". This goes against the technocratic instinct of optimizing everything, but one has to remember about "premature optimization is the root of all evil".
It's my understanding that engaging from the ego mindset "I'm right and everyone else is wrong" operates at an unconscious level when feeling threatened by a viewpoint, which has its roots in "If im wrong, then I don't exist, or Ill die". So when a individual has a strong ego investment in a position, its not really about what kind of view you are coming from on a conscious level because the unconscious mind drives this part. If i am understanding you correctly, I'm guessing you think that all people should be fair and just in their actions. The fact remains that we have this part of ourselves that can short circuit that kind of reasoning and it does drive much of our destructive behavior as a human species.
IMHO Its going to take awhile for the human species to evolve out of that.
I think there's another subtle or not-so subtle effect, which is pure peer pressure and trying to anticipate what will be popular. That is, the system is currently structured such that no one wants to put money into something that won't work. The problem with this is that that's almost required if you don't know what's going on: you have to fund a bunch of studies, 90% of which will fail, to find the 10% that don't. But no one -- absolutely no one -- will get credit for a failed but good attempt at trying something reasonable. So instead people just keep doing the obvious.
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.
In every case I have read about, their reasoning is that money for AS is so scarce that spreading it around means there is not enough for their wrinkle on blocking amyloids. They feel duty bound to sabotage anything that might dilute their thing.
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 too bad all the quantitative easing money isn’t required by law to be directed only at funding basic science research, instead of buying assets. I suspect we would have much better returns.
the investigators narrowing the search for causes honestly believe in what they're doing.
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...
Many of us have been pointing out the amyloid hypothesis was full of holes (heh) for two decades. the counterargument always was "we're looking for our keys where the streetlight is brightest, not building bigger flashlights"
There is no better way to get shut out as a scientist than to disprove the career-making findings of the important people in your field. One of the side effects of this is the “discussion does not match the results” paper. It’s routine to read papers where the discussion blatantly contradicts the papers own results. What is happening is the authors are disclaiming their own findings in order to get past hostile reviewers, betting that astute readers will notice the contradiction, ignore the discussion and draw their own conclusions from the results.
>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?
Lynn Waterhouse, Eric London and Christopher Gillberg have a similar opinion of autism/ASD: see their 2017 letter to the editors of Autism Research, “The ASD diagnosis has blocked the discovery of valid biological variation in neurodevelopmental social impairment”
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.
You could say much the same about depression. As it is, we know there are lots of different conditions all labeled depression, distinguishable mainly by which medication they respond to, if any. (This, despite that symptoms vary widely; e.g. many suicidal, others just lacking affect and motivation.) At least treatments exist, somehow grandfathered in. 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.
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.
I agree with you about depression also being a biologically dubious category. Lynn Waterhouse's publications focus on criticising ASD (and its predecessor diagnoses) in particular, but I very much doubt she thinks the rest of the DSM-5 is all fine–it is simply that autism/ASD is one of her core areas of professional/academic specialisation, in which she's spent much of her career, so that's where she focuses her criticisms.
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.
I agree mostly, but w.r.t. medication, it's not that they have no effect, it's that they seem to function by accident with the most plausible explanation (chemical deficiency?) being suspect under closer consideration.
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.
there was a trend in neuropsychiatry to study "neuroendophenotypes" - the smallest behavioral changes linked to gene expression - rather than treat macro-level diagnoses like autism as monoliths.
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.
> 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.
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.
AD researcher here (late to the thread). As much as I loath the 'cabal' mentality, I personally think amyloid-beta is the cause of AD. Just because a few treatments focused on Abeta haven't cured AD isn't convincing in the slightest that Abeta accumulation is not a causative mechanism. (1) AD is a disease of the elderly - a group not particularly receptive to treatment, (2) AD pathology is likely due to a sequelae that took decades to manifest into symptoms; undoing tens of years of buildup is not going to be easy, (3) even if the treatment could clean up a large portion of Abeta accumulation (and that's a big IF) it wont restore lost memories.
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.
There is plenty of evidence against amyloid-beta hypothesis.
(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.
(1) We know that "pathological levels" does not always result in symptoms across many diseases. E.g. Plenty of people walking around with pathological levels of coronavirus are asymptomatic.
(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.
>However genuine AD diagnoses are confirmed post mortem... inclusion; i.e. AD definitionally requires amyloid presence).
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.
NFT and Abeta are part of the traditional AD diagnosis. NFT studies have seen no lack of funding. But for the record, I do think tau plays a role. I'm not sold either way on ABeta or Tau (maybe both).
"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.
The point is that evidence for amyloid-hypothesis is near non-existent unless you take it as a starting point and do circular reasoning.
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.
And your big brain idea is that it's all about the tangles not the plaques (but not NF tangles from tau mechanisms; it's actually hard to tell because the alt hypothesis you cited above basically say that it's not diffuse Abeta and NTF, instead it's ABeta and NFT inside neurons.
I don't think mixed results from one or two clinical trials warrants a total pivot (see my first post). But, again, I'm not opposed to exploring novel avenues. Anyone who lives long enough will get dementia, so both broad and deep insights are certainly welcome.
Ok, there's more than I knew about. "We found 12 eligible studies in 443 identified records, involving 6736 patients, mean age 71.4 ± 2. We found a small benefit in cognitive outcomes in patients treated with Aβ-mAbs."
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.
I think it would be more accurate to state that interactions between APP and presenilin are very likely causative in late onset AD. Currently the known consequence of that interaction is production of Abeta, ergo the amyloid hypothesis.
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).
ApoE is not necessarily in the a-beta buildup pathway. One idea that was tossed around was that increased cholesterol yielded alkylation factors (like 9Hydroxy nonenal or oxidized cholesterol metabolites) that then modify a-beta but there's not really any strong evidence that that happens in vivo.
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.
One of the smaller pilot trials mentioned has since posted results (n=33). Valtrex administration over 28 days resulted in a (very?) small improvement to cognitive scores (MMSE in the paper):
I'm taking my valacyclovir periodically, regardless. It might be useless. But it keeps the cold sores down.
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.
Acyclovir family meds need to be available over the counter or through a pharmacist. There's actually papers showing that they can be safely taken OTC, and rebuttles basically just saying that "it would set a precedent and increase demand for more meds to be available OTC." To me it's a poster child for the dangers of medication overregulation.
Topical acyclovir is indeed OTC in Taiwan. A largish tube costs about 7 USD. In the US I needed a prescription for it and that same size tube was a couple of hundred bucks.
> For young academics, biotech executive Dr. Raymond Tesi said, "it’s difficult to break into a field with so many strong voices supporting a single target. Alzheimer’s has egos and superstars and big personas unlike anything I’ve seen elsewhere."
For a field with no real results to have "superstars" is a sign of corruption.
"This stifling of competing ideas, say a growing number of scholars, is a big reason why there is no treatment for Alzheimer’s."
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.
The idea of an oppressive scientific elite is a bit too neat and tidy. Certainly there are banal human politics at play, but it's hardly an explanation for all that ails. This idea is too attractive to the heterodox and outsiders cynical of scientific institutions.
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.
Question for those who know: is this a problem in general with the culture of academic science?
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.
Yes, it is a problem in general. It is inherent in the system that issues grant money and permits publication according to the opinions of the "old guard" in each field.
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.
Yep. Its happening right now with Long hauler research for Covid where 19/20 of the top papers explaining the condition were not NIH funded. The NIH is so far behind in terms of research compared to organisations that are publicly or privately funded that its almost laughable and its controlling 1.1 billion USD and getting nothing done at all.
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.
I'm not in the know, but what little I know of science history tells me that entrenchment is a regular occurrence in the sciences, going back to Copernicus and Co.
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.
The amyloid hypothesis is such utter bullshit, at this point there have been empirically effective anti-amyloid plaque drugs. That is drugs that effectively and measurably reduce amyloid plaque build up. None of those drugs have impacted Alzheimers symptoms in any way.
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.
You may be correct, but there is another model whereby the damage to the nerve cells is done by the build up of the plaque. Removing the plaque does not necessarily repair the damage.
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.
They just mean that there is some insulin dysfunction with Alzheimer's. They don't really know how important it is both from a symptom or cause standpoint.
I will take a really risky guess on the premise that there are many different types of causes for Alzheimer's. But one type of them might be caused by parasites. And it's either the body's response or an intended affect of the parasite to enclose the parasite in a type of plague. Kind of like biofilm... or both. Reducing the plague or biofilm could allow the immune system to respond to it by "seeing" it... in some cases. It might also allow the parasite to grow faster if the immune system isn't successful or can't see it. Based on my guess, a treatment plan would involve biofilm/plague "breakers", fasting or behavior changes to reduce and eliminate parasite's life cycle, and anti-parasite medicines that can reach the blood brain barrier. Again, I think there are different types of causes for Alzheimer and this is just one cause.
If you’re saying Lyme disease, at some frequency causes alzheimers, then it should be observable in different incidences in alzheimers between the US and countries that, at least now, are considered free of it such as Australia. To my knowledge there is no difference in incidence
I have read that metals like aluminum, copper, zinc, and iron can play a factor in the onset of Alzheimer's, but that might be related to the amyloid plaque theory.
I regularly take zinc and iron supplements and have used aluminum based deodorant, so I hope there's no relationship!
It would be interesting to see the correlation in families with a history of diabetes, and to correlate it to T2 diabetes or "metabolic syndrome". I have anecdata about this, but I wonder if any studies are being done in family-groups, such as identical twins etc.
Pharma has sunk billions into the amyloid hypothesis, fielding multiple candidates to no avail. Good money thrown after bad. Huge market need, has to go back to working out a new animal model. Self-delusion at it’s best, or blind optimism with “this time, it’s going to be different”. Lucy and Charlie Brown snd the bloody football.
I have not heard of aluminum being a cause but have heard other toxins such as heavy metals as contributors for certain types of Alzheimer’s (“The End of of Alzheimer’s” by Dr. Bredesen)
"Trust the science" has been a often drummed mantra the past several years but it's important to consider science is subject to bias, group think, influence, and sometimes corruption. (although the latter doesn't seem to apply here)
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.
The fact that researchers can and will speak out against consensus is exactly why I do “trust science.” I don’t trust consensus theories to be accurate at every instant in time, particularly in areas that have received more limited scrutiny (or where experiments are expensive and time consuming), but I generally do believe that it’s the very best process the human race has ever devised for arriving at truth.
>> The fact that researchers can and will speak out against consensus is exactly why I do “trust science.”
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.
>Recommending against masks early ... 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.
That is the ideal, sure. In practice though, science is whatever scientists do.
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).
These are not science problems, these are human problems and the breadth of human endeavor is crippled by them. What is unique about science is that it acknowledges these problems and has mechanisms to address them.
I agree these are human problems, but in my experience science doesn't always acknowledge them; sometimes they're even worse because of a false mask of objectivity. In theory there should be mechanisms, yes, but in practice it's often very different.
For sure. The easiest person to fool is yourself. But again I think the primary thing science has going for it is that it at least acknowledges that humans have these problems. I’m not aware of any other field of human endeavour that does the same.
Well, that's the problem. There is no "science" as a separate entity from the humans who practice it. So, science can't acknowledge these problems and fix them, only people can. For that reason, I don't think it's useful to distinguish the abstract concept of Science from the actual human activity of science in this case.
it's important to know what you're trusting. in, say, the thiomersal controversy, the hypothesis was that thiomersal causes autism. many studies were done. there's no link to autism. you either trust the science, or assert a conspiracy between dozens of independent groups to straight-up falsify data, and to what end? so yes, I trust the science on thiomersal. the same way I trust the science on covid vaccines.
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.
Was there a lot of controversy among the scientific community ? The experts seemed to all say pretty much the same thing - masks indoors, social distance, get vaccinated, etc.
All sorts of places, including some unlikely ones. California, Massachusetts, Maine, and Texas all pulled licenses for refusing to uphold the narrative.
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.
HCQ was an interesting thought in early March 2020 (my brother as an ICU doc was considering getting some for our parents). But the data was very quickly available that it was essentially worthless, and certainly nowhere near as useful as some other cheap, off patent medication such as steroids which was rapidly demonstrated to be highly effective at cutting mortality by the UK’s medical industrial complex.
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
People suggesting ivermectin ought to be interesting were not wrong. It could plausibly have had some effect, based on the biochemistry.
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...
Noone was going after researchers running proper studies with informed consent on e.g. ivermectin impact on Covid. However, doctors randomly prescribing stuff because they believe in it is quite different from a medical study - we have good historical reasons why we regulate medical experiments on humans, why we don't allow the medical and pharmaceutical industry to "just try it" unless certain conditions are met.
Which doctors specifically are you referring to? There really wasn't any scientific controversy about the effectiveness of these drugs, it was mostly social media controversy by non-scientists.
The fundamental difference is that science explicit recognizes bias and dogma, and works to identify and (to the best of our ability) eliminate its impact on our conclusions. For example- recognition of various biases leads scientists to use randomization and blinding and often scientists have to conclude that they were wrong because the data simply showed their hypothesis was very unlikely.
One might wonder if a similar thing had been happening with low carb / keto diet research. Being adopted as a fad diet has overwhelmed the constant scorn from the nutrition community.
I think the "cabal" hypothesis is stretching it too much (especially where a malicious element is implied).
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 ..."
> as Aisen put it last week on the sidelines of the Aspen Ideas Festival, “I don’t think I’m part of a cabal.”
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.
Surprisingly large amounts of people are lazy, and copying whatever was done before and changing up the words a bit covers most everything most of the time.
Yep. I've been lucky enough to work with a few people who are (mostly) open to hearing evidence they don't agree with. It forces you to up your game, for sure.
It's always harder to convince them than when they already agree, but at least it's not impossible.
Institutions blossom based on the work of individualists. They try to make a good foundation to keep the good going. Later on the institution gets corrupted, bogged down by parasitic people and eventually must be burned to the ground, perhaps by the work of, again, brave rare individuals
I have a dog in this fight as the founder of neurotech/sleeptech start-up https://soundmind.co, however we are NOT looking at an Alzheimer's treatment, but rather prevention.
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.
This is why we need more funding for biomedical research. Some proportion of those additional funds need to be distributed on a consistent basis to long-shot or unexplored hypothesis research.
The issue is that politicians have for decades described this sort of research as "government waste".
I think we need a restructuring of the process by which funds are allocated, not necessarily more money (although I'm not opposed to that).
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.
I don't believe there is more to it than the researchers getting exploration/exploitation wrong in this case.
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.
Some say that string theory gets much of its pull from physics departments who favor string theorists as faculty who do not need and will not provoke lab work.
There's always methylene blue under development by TauRX and in stage 3 trials. https://taurx.com/the-science/clinical-trials. Even more amusing is that you can take methylene blue right now as Troscriptions sells a non-prescription product containing pharmaceutical-grade methylene blue intended by the manufacturer for human use. Yes, your tongue will turn bright blue.
I would bet money that alzheimers will eventually be found to be primarily caused by either a 50+year incubation period transmissible disease or by pollution.
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 think we're seeing a similar thing shake out with atopic dermatitis, long thought to be related to type 1 hypersensitivity but not treated by antihistamines and poorly treated by steroids. The development of JAK inhibitors has created a new industry in treating many types of immune mediated disease and I have not seen the immunology texts rewritten yet.
The development of JAK inhibitors for dermatology was not limited by any hypothesis but because of the multifaceted risk conferred by JAK inhibitors including increased risk of cancers.
Committees, like all decision-making entities, are sure to make mistakes. This is a good argument for multiple independent funding sources for research.
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.
As much as this is a good story, I don't think the Amyloid hypothesis has been disproven yet. We have several very large phase 3 studies in the pipe, with results expected in the next few years. If they all fail, it will be pretty clear. But we're not there yet.
It is easy to discount the amyloid hypothesis and amyloid research based on the facts that 1) amyloid is not required for neurodegenerative disease pathology, 2) many people who do harbor amyloid fibrils/protein plaques do not exhibit neurodegenerative disease pathology, and 3) amyloid-reducing drugs do not seem to affect neurodegenerative disease progression. It is also true that amyloid is an enticing target for a lot of people with vested interests in this area and those interest may have put too much emphasis on amyloid itself. Like most things in biology though, there is more to the story.
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.
According to Derek Lowe (in the pipeline), who has written on this at length, none. Other than the fda approving drugs that did not show efficacy that will suck money from Medicare and give families false hope.
Is there a chance we take it as a teachable moment and ask ourselves if there are other areas where we feel OK to suppress alternative approaches and ideas, and where we're going to pay dearly for it later?
It's all over really. Alzheimer's is sort of an interesting example, but not really fundamentally different in a lot of ways from other areas. Some sure, but some not.
Indeed, really the Alzheimer's situation is unusual only by virtue of being a politically controlled narrative without being partisan.
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.
The only really promising treatment effect I have seen in recent years was in a huge, broad study of Veterans Administration patients (N tens of thousands) conducted over a 6-year data set.
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 sort of correlations a lot and I have to wonder, is this a wealth predictor? That is, is it that someone who is more likely to get their TDAP is also likely has a more stable life.
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.
That kind of confounding is something that it is well understood how to filter for, by matching cohorts. It is possible when N is in the tens of thousands. But their report did not say the effect was more pronounced in any particular selection of cohorts, other than as noted.
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.
The evidence is inconclusive not negative. That trial was halted but later restarted. There is some evidence that it works, and this is better than any other potential treatment which has not shown any evidence. And alzheimers is a fatal disease
Aduhelm is also a potentially fatal drug. Even ignoring cost, evidence that the tiny amount of good that it might do exceeds the clearly evident harm it can do is, to put it mildly, lacking.
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.
My pet hypothesis is that Alzheimer's is the effect of fungi on the body. I think depending upon genetics we have a certain resistance and as we age it weakens. Possibly early onset Alzheimer's could be any factor of exposure levels throughout one's life and or from genetics possibly weakening the resistance of the body towards fungi. While the type of dementia that most elderly develop is possibly the outcome of long-haul exposure to fungi. I've already read some research between fungi and Alzheimer's but not all. I'm just someone who has/had family members with the illness and I'm curious about it. edit: whoever downvotes me, please reply because I'm very curious on if you're downvoting for any specific reason from research that makes you highly doubt my pet hypothesis.
I didn't downvote you, however I think people may dislike the idea of one having their own pet hypothesis without linking serious evidence to back it up. Amyloid plaques have been heavily studied and may have some tangential but real link to Alzheimer's, it's a plaquey protein found in the brain along with Beta-Tau which is another protein I believe. I personally haven't heard of any fungi theory yet, the main ones I've heard were viral things, pollution, or perhaps some breakdown in the brain's ability to clean itself up over time. And why are certain individuals spared and not others? I know there are genes that predispose one to it, and there are early-onset cases which come on more often than others.
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.
I don't think we should discourage people from having a pet hypothesis if they're open about it. I seriously doubt that in academia most don't have their own pet hypothesis. I think the problem is when persons aren't open about whatever being their pet hypothesis and or even deliberately going out of bounds on what's acceptable based on their own pet hypothesis. As I said to another person that replied to me, you can google "fungi and Alzheimer's " to easily see the research in great detail. Maybe even visiting researchgate and doing the same. Also thanks for replying because I do have family members that have it.
Most pet hypotheses of researchers are informed by actually knowing about the disease, and not disregarding things such as 1) years of schooling (protective) 2) early onset alzheimers (genetic) 3) APOE2 (protective) 4) APOE4 (higher risk) and the multitude of other factors.
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
I think people are acting unfair towards me if what you're asserting is the cause of the behaviour. Unless my interpretation and expression of a "pet hypotheses" was truly wrong of me to do. Since I don't think writing about one's pet hypotheses is making a claim in what would indeed warrant negative behaviour.
So we're suppose to provide 'research' if we downvote your 'hypothesis', but you can just toss it out there and expect us to take it serious without the same consideration.
I'm not arguing against downvoting if someone believes what I did is actually against hackernews if it truly is? My edit expresses how I would be grateful for anyone informed in the research to explain if they obviously disagree enough to downvote me. They would've likely read what I've read anyhow on the fungi & Alzheimer's research.
I've been reading research on Alzheimer's from the start of when I became informed about my family members having it. There's multiple approaches that research is going over of course. Some is on fungi like what my comment asserts. If you do a quick google search you can read about it in great detail.
“The End of Alzheimer’s” by Dr Dale Bredesen mentions mold as one vector, but I don’t recall fungi as one. Key insights from that excellent book are that there are several different types of Alzheimer’s, each with a different cause. Other causes have been mentioned in these comments but not all and not comprehensively.
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.