The major problem has been lock-in of the Abeta 42 peptide fragment as the cause. This monomaniacal focus was rewarded by grant awards to team players.
Karl Herrup has a terrific book on the topic How Not to Study a Disease — The Story of Alzheimer’s from MIT Press (2021, ISBN 9780262045902). He did not win many friends but I think he is right.
The consensus now is that many factors contribute to the heterogeneous diseases we now call Alzheimer’s.
The article (or I guess more accurately "podcast transcription") seems to be saying that this lock-in essentially happened due to fraud, since some of the data was intentionally doctored to get the intended result. One of the guests seems to be an author of a different book about this (with the other guest being the scientist who apparently uncovered this). I can't personally attest to the accuracy of anything they said, but they're at least alleging that it was a lot less benign than it sounds like you're describing.
The focus is definitely on scientific fraud, but what makes the fraud so easy in this case is singing and selling the same song that the big teams are singing and selling. You can fly under the radar AND get funded, and if you are “lucky” become an ultra big shot like Masliah at NIA.
I don't buy the fraud explanation as the full explanation. Other areas of medicine (stem cell) has had bigger incidents of fraud on top of other major headwinds, and still has made more progress.
Fraud is everywhere and we still move forward in most arenas.
In ALZ and the plaque cartel the fraud was foundational and the overwhelming source of funding for research was tied to supporting that hypothesis. The big issue, even if you have a competing theory, is that the diagnostic criteria relies heavily on the plaque and presence of indicators. So you get a group of people who have elevated plaque and MCI, but many people have elevated plaque without MCI, and just as many people have MCI without elevated plaque.
So if your cure is targeting something different but the group of people you have are selected from this cohort of maybe afflicted people then it's really hard to get a significant result. Plus you tend to be dealing with old people, that have other health issues that MCI isn't causing to get any better.
The stem cell field is also quirky. IMO it is one of the most cutthroat, competitive, ruthless fields of life sciences that is new enough in history to still have a bunch of pioneers fighting to be the figurative Oppenheimer. One PI’s fraud is quickly detected and fought over.
Meanwhile the Alz and Neuro field as a whole are well established, and the amyloid hypothesis was a foundational theory taken as a fact. Any initial questioning of this and they would brand you as a lunatic.
There’s another book mentioned in the podcast called “Doctored.” The gist is: bogus “science” led to loads of money / research going in a direction that was effectively fiction.
People love to praise “the science” when they mean the scientific method. What they always seem to forget is that method is executed by humans. Imperfect, sometimes ego driven humans.
Elaborating a bit - brain is hard to study since you can't easily take a biopsy of it (from a living person at least), and various brain scans are not great at identifying the stuff we care about.
The slow acting nature of it means also you have to wait a long time to see results of clinical trials; also because early stages are easy to miss that also means you are stuck studying people who are already pretty senile and thus might be beyond the point where you can make a big difference.
Ruxandra has a nice piece, focused on cancer, but the reasoning is basically the same here: biology is just really hard. Sometimes we get lucky but in general it's a long, slow slog.
And as with a lot of cancers, it seems to be perturbation of a dynamic system rather than a single, mechanistic cause.
Think of it like brushfire in an ecosystem, or species population imbalances leading to catastrophic breakdown. These are better understood in terms of system state and preconditions, as opposed to a trigger event.
Infectious disease, at least in the classic acute form (whether that's bacterial and fast - cholera - or viral and slow - HIV), is a more mechanistic process which can be halted by blocking a single step in its pathway.
Systems that remain healthy and balanced via dynamic processes are harder to reason about and fix, because the root cause of a disease state can be dozens of little things adding up to the system losing its ability to maintain homeostasis.
Its done substantially better than more common diseases like ME/CFS which very few have even heard of let alone know the symptoms of and receives almost no funding at all. Alzheimer's received a further $100 million of NIH funding earlier this year (https://www.alz.org/news/2026/100-million-dollar-alzheimers-...). That is 6 times the total funding for ME/CFS federally which is currently just 15 million and planned to decline.
The research went awry in Alziemer's due to fraud but its being funded at a reasonable level, a level many with Long Covid or ME/CFS or Fibromylgia would be very happy to see but doubt will ever happen. Funding of diseases is not "fair", it isn't based on number of sufferers * quality life years lost and we should be spending more on medical research generally. Alzeimers is one of the better funded diseases in the world.
'Science progresses one funeral at a time...' It is often the case that an entire field is led by a few influential people and until they leave others can't get the air they need to make real progress.
I'm not saying I'm the best informed on this topic, but I thought the root cause has been known for a long time now as degraded endocrine and cardiovascular function.
That's also why Alzheimer's can take so long to develop. It's just one aspect that we've chosen to focus on because it's more clearly noticeable, but it cannot easily be treated in isolation from everything else. If it was, it would regress quickly without fixing the root causes.
We truly do not know the root cause. There are plenty of folks with "degraded" endocrine, cardiovascular, and both systems. Most of them do not develop Alzheimer's.
There is no single root cause. Many scientists have preferred to ignore this fact and that has been a serious problem. Everyone likes a simple story. Age-related diseases are not simple stories.
> gatekeepers directly or indirectly control research funding.
Perhaps funding like public grants could be controlled by few? Should not the case for private money?
Relatively common health issues older people tend to get fair amount of private funding after all.
Rich people tend to be older and they are lot more likely to see amongst their friends and family Alzheimer's and Parkison's or even cancer and so forth and be worried about it and thus donate money to them.
In somewhat related (i.e. old people health concerns) life extension research gets all kinds of wacky non traditional research lines get funded all the time, I don't understand why would Alzheimer's would be any different.
If you're a wealthy person lacking a neurobiology background, how do you decide which research efforts are the most promising? Which labs do you back?
Generally, you rely on experts.
Who typically became experts by adhering to the conventional wisdom set by gatekeepers.
"Science advances one funeral at a time" feels apt.
Sadly, the problem isn't confined to Alzheimer's.
Whenever only a few people decide what is "right," the same pattern of stifled innovation will generally manifest itself not by design or from malice, but because it's hard for a small group to be 100% right on what works and what doesn't -- especially on matters as inscrutable as neuroimmune diseases.
I don't think the problem is nearly as big as people claim. Experts are often right!
While there are counter examples and inefficiencies in the system (and there are idea of addressing this, by distributing some part of the money in other ways), we have far bigger societal issues because people do not believe in science, especially where there is an industry lobby sowing doubts.
So I really want to push back against the the idea that the scientific system is broken. While there are real issues, this is still very misleading.
What also happens is these gatekeepers end up being those requested to review papers. When a paper comes up for review that challenges the status quo these gatekeepers nit-pick the paper and recommend it not be published. This happened to my wife on numerous occasions. She has a few unpublished papers because of this. What she found in her research has since become the common accepted knowledge in her field after a few funerals.
Life extension seems like the kind of thing that can get private funding with relative ease specifically because they aren't trying to compete with the government. There are a lot of private foundations that give out grants too though.
Life extension in the private sector is dominated by hocus-pocus and unwarranted optimism. The genetics of mortality is amazingly complex. See this open access monster paper that came out in Nature this week—admittedly “in mice” on mortality and genetic of longevity.
In most engineering fields we don't give the monopoly to people until they have actually demonstrated success beyond a reasonable doubt. There will always be groups of people claiming that the math/methods they happen to know are the best at explaining some behavior (even now there is that learning mechanics paper on top page)
The takeaway is to stop pretending that we can do good science when the ambiguity is so high, the majority of funding should go to people working on more concrete problems. We never locked in on vacuum tubes because the downsides were so obvious and the upsides of silicon transistors (if they could be made to work) were also obvious even to people outside the field, where your talent comes from. At the very least funders can't allow shifting goalposts, make them up front answer questions about the drugs. That will give you something to estimate the value of the drug and then when they come back with study after study outside the ranges they gave, you lower their funding. E.g. This is supposed to work on someone who was stage 2 and stop progression and then 5 years later it only "works" for stage 1 patients.
Strange breakthrough ideas can't even exist in the current system structurally, so going this route is the only logical choice. Which begs the question, why aren't clinical trials a private venture already? Governments are burning billions of taxpayer dollars for either nothing or cynically to keep the boomers alive and voting even longer, while 1/5 children are obese. For the rest of us we've socialized the risk and privatized the profits.
Type-3 diabetes? It's degraded endocrine and cardiovascular functionality. Basically, your enzymes stop producing -- things like testosterone and insulin. Your lungs stop working as efficiently, and your brain just gives out.
If you're looking to beat type-3 diabetes, you need to have a daily routine of exercise while you're young to keep these systems in shape when you're old.
You also don't need to belong to any marginalized groups, as ACEs tend to wear your body out over time -- breathing, kidneys, and heart in particular. People with traumatic childhoods (bullying, abusive parents, etc) have a huge risk of dying of dementia -- if their kidneys don't give out first.
Alzheimer’s is a good example of a disease where we don’t have great scientific understanding on the underlying causes, but that doesn’t stop individuals from believing they understand it better than the scientists.
Actual Scientists are calling it Type-3. But these are the same scientists that are actually reversing Type 2 diabetes without expensive drugs. Of course they exist outside the pharma narrative, and they don't have any uncurious attack dogs willing to defend their narrative-busting results.
Are recurrent childhood neglect and abuse events not an antecedent to mental health morbidity in adulthood, which then creates missed opportunities for growth and necessitates and the need for the use of medications?
I think you’re making a giant leap from A to Z and missing a whole bunch in between.
All I know is that people with higher ACE scores have higher dementia rates. And that higher ACE scores are linked with heart failure, lung failure, and kidney failure.
Stress ages the body. Homeless people can age several years, being on the streets for just a few months.
I've also seen numerous people in these upbringings die in their 50s and 60s from kidney failure. My stepdad was one of them. My father too.
My father had a normal childhood, except he had a traumatic experience of shooting his twin brother while they were playing cowboys and indians. Spent his entire life blaming himself. Went through all the normal development phases. Not on any meds.
His body just started shutting down prematurely. It's common in people with those experiences. First, his breathing got bad. Then his kidneys. Then he started having heart problems.
And that's the pattern. Heart, lungs, kidneys. Which are all linked to the brain. And eventually lead to dementia-like symptoms. At least that's what the research on ACEs seems to point out.
Because of Joy, scientists developed a simple, non-invasive, three-minute skin swab test that analyzes sebum to diagnose Parkinson's. In laboratory settings, this test has shown an accuracy rate of over 90%.
Unfortunately that insight hasn't led closer to a cure.
It also turns out sort of bad to tell people they have a horrible neurodegenerative disease 10 years before the major symptoms start.
Why isn't everyone's mind blown? Well for the cynical explanation, look at the state of science education and what people said about Artemis, vaccines, etc. or optimistically, there are too many mind blowing discoveries to treat them all fairly.
They had a biological model. They had multiple drugs that were showed activity against that model, and effectiveness in humans. Problem was, the model was wrong. Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable.
Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most guesses work to some degree to keep pharma alive - otherwise nobody would fund the business.
Edit: Google the in the pipeline blog. This and other have discussed this at length.
I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation.
Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.
The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show".
Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
"Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles"
Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this
"The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. "
Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
It is worse. The code changes are mostly random, only surviving the tests of fitness nature is applying (on various levels though; immediately catastrophic changes on level of cell biology are sorted out). And at least the high-level tests are also random and unreliable.
So basically it's a codebase mostly composed of bugs, and the features mysteriously work because they're based on bugs that happen to be mitigated by other bugs. :)
>there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality.
Is that supposed to be an endorsement or a dismissal? The ostensible goals of "rationality" seem like good things, so it sounds like an endorsement, but in the wake of the FTX/SBF fallout they got a bad rap.
For you, simply listing the author of the post is enough to discard it. Not everyone is that well informed, so it would be helpful for you to add another sentence explaining why this author has no credibility with you.
By this logic, we wouldn't have some of the breakthroughs made throughout history. Outsiders have made some pretty interesting leaps (later honed by experts). Expertise is great, but it can exist outside of formal education, and it isn't the only metric.
Many in this thread, who have evidently spent very little time studying the topic, have confidently concluded the experts are wrong.
I, also a non-expert, spent six months studying what the experts are doing, concluded that they actually seem to know what they’re talking about, and shared my understanding of that with other non-experts.
If you’re going to dismiss me for saying the experts are right, since I’m
not an expert, then shouldn’t you dismiss those who spent far less time than I to learn about the subject, who are saying the experts are wrong?
Ha! You must be using a different username than I knew you by then. Hit me up on one of the many platforms we’re probably both on if you like, would be good to reconnect.
It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations.
> I thought despite the fraud, it's still the best model we have[1]?
It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines.
The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms.
So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender.
>> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise.
I fully agree with your point, though, just not the example.
Over the past decades the group that are not happy with the AGW consensus in the hard earth sciences crowd have principally funded FUD via think tanks, ala the pro-tobacco lobby back in the day, rather than research.
The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts.
The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world.
Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt.
It's all about money, power, and entitlement. Not about truth or responsibility.
But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.
Expecting scientific rigor is not a bad bias: everyone who has been willing to do actual science agrees that climate change is real and significant. For example, Richard Muller was a climate skeptic who had a great job at one of the most prestigious universities in the world, got funding to establish a team to critically review climate science research … and concluded it was right:
“When we began our study, we felt that skeptics had raised legitimate issues, and we didn’t know what we’d find. Our results turned out to be close to those published by prior groups. We think that means that those groups had truly been very careful in their work, despite their inability to convince some skeptics of that.”
If you haven’t read up on both, it’s hard to appreciate how unlike climate science is from the beta amyloid theory. The latter has some evidence but there were always alternate theories by serious researchers because it involved multiple systems which scientists were still working to understand and basic questions around causation and correlation had significant debate.
In contrast, climate scientists reached consensus about climate change four decades ago and by now have established many separate lines of evidence which all support what has been the consensus position. More importantly, since the 1970s they have been making predictions which were subsequently upheld by measured data from multiple sources. The ongoing research is in fine-tuning predictions, estimating efficacy of proposed interventions, etc. but nobody is seriously questioning the basic idea.
Almost all of the people you hear dismissing climate change are funded by a handful of companies like Exxon, whose own internal research showing climate change was a significant threat produced a chart in 1982 which has proven accurate:
The comment you were replying to was talking about funding. If you could develop a scientifically plausible model to defend the "burning fossil fuels is not so bad, actually" thesis, your funders would include the oil companies and the greater petrochemical industry. There is a lot more money to fund projects there than... anywhere else in the world, really, by a wide margin.
well oil companies funded "lead fuels are safe" research...
...and it really did backfire (in public relations, politics, etc)
now... I don't think they can actually fund 'research-for-their-profit' -- I mean, would you believe "petro is good for earth" research coming from oil companies, even after the 'lead is good or neutral' research?
Not uncritically, but if the research presents a logically consistent hypothesis, and evidence supporting it, then it would be worth following up on with independent groups and if it remains consistent to scrutiny then it should be accepted.
There are so many counterexamples proving that your statement is just not true. I'll give you just one example, the Berkeley physics professor Richard Muller that took funding from the Koch foundation to attempt to "prove" that the satellite temperature data was "miscalibrated" and estimates of actual warming were overblown. Started the project in 2010. First published in 2011 showing that in fact the warming was real and using more advanced calibration techniques actually showed the warming was worse than we thought.
having worked in amyloid, and in an a-beta lab in the second half of the 2000s, we always said under our breath in group meetings that we were skeptical about the amyloid hypothesis, but our grant applications certainly did not say that (or if they did it was a quick throwaway sentence). And I think the lab that I landed in was one of the most honest scientific labs in biochemistry/chemical biology.
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
Edit: I see you specifically pointed out "predictions of catastrophe", which if that is true (and not just the position of radicals on Twitter) is indeed unfortunate.
Yes I believe GP was focused on the catastrophe part. It's very likely correct that our CO2 emissions are warming the atmosphere ocean etc, but it's not clear that runaway warming is inevitable or that life or geology have feedback mechanisms that turn an exponential into an S curve. That is, after all, basically what natural selection tends to do. Turning the table again, even if there are corrective factors humans might have immense suffering before it stabilizes. So we don't know.
You didn't ask, but my opinion on it is that we'll probably stabilize on a cleaner energy source and find natural countermeasures when suffering ticks up. Any top down pressure to change things whole cloth seems doomed, no matter how benevolent. We're closed loop creatures.
> There are also money issues like with the alzheimer's situation. (that is: If climate change is dooming us then we should send more money to climate scientists)
Absolutely, the issues are similar
And if this can upend the business model of some big companies we'll give some "incentives" to some "doubtful" scientists even if their doubts are unfounded (actually very well founded but you get the gist)
Which sucks because such work should be free of pressures and incentives
> we should send more money to climate scientists.
Couldn't disagree more.
Please spend it on those who might actually fix something.
There's plenty of can remove carbon or can undo the effect of X on Y. Let's stop falling back on the bad argument of we must leave nature alone right after arguing we change billion dollar industries because we can.
We shouldn't learn to be custodians watching the planet die because of past mistakes, we should be fixing and improving the planet and improving on nature because we can, must and should, shoulder this reaponsibility.
Please not _yet more modelling_ burning HPC into the ground just for a crappy bar line graph (based on assumptions)...
> we should be fixing and improving the planet and improving on nature
How do you do this without a process of finding out what works and what doesn't? Isn't that science? Or am I misunderstanding you saying no more modeling to mean we already know everything we might need to know in order to shoulder this planet scale responsibility and just collectively aren't doing anything except making bar charts?
What does your proposal actually look like without science or climate modeling?
I am baffled by the number of people on HN, presumably a website for and by technical people, who fail to consider secondary and tertiary effects when it fits their worldview to do so.
There is a yawning abyss of states in between extinction and 'boy sure is a few degrees warmer out here' and none of them are good.
Many organisms would benefit from a warmer climate, just not humans.
We rely on extremely narrow conditions for the fragile supply chains and power structures that keep us on the ragged edge of civilized to continue working. We had an extremely mild contagious disease outbreak, by historic standards, and our economy is still feeling the effects!
Imagine the impacts of something like wildly different rainfall patterns, increased rate of global infectious disease, shifted agricultural zones, changes to Jetstream patterns, large scale crop failures, loss of water supplies, temporary local ecosystem collapses etc. These changes are incredibly fast on the scale of what it takes to reach ecological equilibrium.
These of course mean nothing to biological life, writ large. Life will recover and adapt. To fragile human civilization they mean refugee crisis, resource wars, failed infrastructure, and ten thousand other existentially terrible things.
I get your point but on the other hand humans live quite well in places like Medicine Hat say where it swings from -40 C in winter to +40 C in summer. Against that the likely warming by say 2100 is I think 1.5C up from what it is today which might be just about noticeable?
Did you read the post at all? Second order effects, not primary effects. Its exasperating how much effort people will put into not understanding the smallest things when they are inconvenient to their worldview.
> If climate change is dooming us then we should send more money to climate scientists.
Depends! If you're a large fossil fuel company, the obvious move might be to spend more money on advertising agencies scientists, or entire foundations who question climate science instead.
Yes, there is overwhelming evidence of climate change. And that we are causing it.
However research into what we humans can do to ameliorate it is verboten. For example https://www.scientificamerican.com/article/fertilizing-ocean... was an actual experiment that found a low cost way to both remove lots of CO2, and improve a fishery. But that line of research has been shut down.
Likewise research into the current impact is only allowed if it agrees with what is politically correct. For example many researchers have found that current severe California forest fires are mostly due to poor past policies, that have resulted in very dense forest, with a large fuel overload. But research that stresses the impact of climate change are easier to publish, and this shifts the apparent consensus on the causes of things like the major 2025 fires in the Los Angeles area.
> The project is also unlikely to bury much if any carbon dioxide for one simple reason: metabolism. As other iron fertilization experiments have shown, it is relatively easy to get plankton to bloom, but it is harder for that bloom to sink to the bottom of the ocean, where it takes CO2 with it.
Do you really think that adding iron releases net carbon? That would be hard to explain chemically.
The worst case scenario laid out in that article is that most of the carbon absorbed, was later rereleased. So net zero carbon, not net carbon emitter.
I've seen other reports of that exact experiment that estimated a significant net carbon sink. The actual experiment failed to make measurements that lets us know which actually happened.
Regardless, we've certainly demonstrated that, at least sometimes, there is significant net carbon capture, at low cost. Given the certainty of global damage at present, I believe that this justifies continued experimentation. Even if it means accepting possible risk to local ecosystems. The local ecosystem can generally recover. The planet, not so much.
You think the chemical compounds were just magiced into the ocean with no carbon intensity. It literally says carbon will not be absorbed and that geoengineering is not the goal.
> There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
With any position, you have to distinguish between its thoughtful advocates and its thoughtless ones-every position has both
Any thoughtful “climate change sceptic” is going to say (a) of course the climate is changing-it always has and always will; (b) of course it is implausible than human activity has literally zero impact on that change. But that still doesn’t tell us: (i) the relative scale of anthropogenic versus natural causal factors; (ii) the validity of any specific predictions of future change; (iii) the likely socioeconomic impacts of any future changes that may occur. It is totally possible that a person may affirm (a) and (b) while questioning the “consensus” on (i) and (ii) and (iii)
Personally, I don’t have a strong opinion on the substantive issue - but I wonder about the extent to which mainstream discourse on the topic represents good epistemic hygiene. It is even possible that the sceptics are on the whole more wrong than right, but simultaneously the mainstream response to them is more irrational than rational.
For Climate Change it's a question of opportunity costs. With expected inputs how much will temperature change? What are the effects of that change? How much effort to you put into changing the inputs? How much effort do you put into dealing with the effects?
The biggest difference is that Climate Change is a deeply political question with a bit of science tossed in. Alzheimer's is the mirror opposite - it's a scientific question with politics added to the same degree of most other things.
The problem is that the top researchers in the field have spent their lives devoted to amyloid beta. They may well have helped direct hundreds of millions in grants to this line of research.
The idea that they have blocked the treatment of Alzheimer's rather than helping it, is very, very painful. This is perfect for creating cognitive dissonance.
And so, no matter what the evidence, they remain committed to the conclusion.
As a result, the latest Alzheimer's drug to enter stage 3 FDA trials is Trontinemab. (It is currently in stage 3.) It targets the amyloid target.
A relative drop in the bucket is going to, say, the infection hypothesis. This despite the fact that the only intervention that has been shown to reduce the incidence of Alzheimer's, is the shingles vaccine.
Hah! What do you call the cap and trade group? The whole trillion dollar "carbon credit market" is a farce built to profit from climate change catastrophism.
Small change compared to global fossil fuels. Energy (which is still mostly fossil fuels) is 10% of the world GDP.
Climate-change denial is just like tobacco-cancer denial. It's the same banal "I win, you all lose" mechanism. Enormous resources are available (along with the useful idiots) to propagate falsehoods.
You are mistaking the beneficiaries here. Carbon credit scheme is indeed a greenwashing scam and it is pushed by the oil and gas (plus adjacent) industries. It is plainly obvious that shuffling emissions between jurisdictions does jack shit against reducing the actual real amount of emissions to the atmosphere. Basically the main proponents of the carbon credit fraud are the same people financially motivated to reject long term climate change consequences (aka anti-"catastrophists" in your lingo).
If cap-and-trade held the same levels forever you would be correct. But all of the cap-and-trade systems I am aware of have a built-in lowering of the cap over time. So they start out doing nothing/very little, then ramp up to meaningful reductions over time.
The idea being both to make it easy to get people to agree today (the reductions are tomorrow's problem), and to allow time (and foresight) for industry to adapt to where things are going.
The Amyloid hypothesis persisted for so long because we didn't have any obvious counterarguments since it is so hard to do studies on the brain. Which also means that it's not a bad hypothesis.
What happened is we got the tools to start studying viral associations with other diseases and ... whooops ... suddenly there are associations. The shingles and RSV vaccines seem to affect dementia while others like influenza don't.
Now people can ask questions about why those particular vaccines affect dementia while others don't. And suddenly we have falsifiable tests.
Now we can subject all hypotheses (including Amyloid) to stronger scrutiny.
There were no cointerarguments? There was a very simple counterargument: where was the causal data? If none exist why should I counter argue when you hadn't proven it to begin with.
Karl Herrup has a terrific book on the topic How Not to Study a Disease — The Story of Alzheimer’s from MIT Press (2021, ISBN 9780262045902). He did not win many friends but I think he is right.
The consensus now is that many factors contribute to the heterogeneous diseases we now call Alzheimer’s.
Fraud is everywhere and we still move forward in most arenas.
So if your cure is targeting something different but the group of people you have are selected from this cohort of maybe afflicted people then it's really hard to get a significant result. Plus you tend to be dealing with old people, that have other health issues that MCI isn't causing to get any better.
Meanwhile the Alz and Neuro field as a whole are well established, and the amyloid hypothesis was a foundational theory taken as a fact. Any initial questioning of this and they would brand you as a lunatic.
People love to praise “the science” when they mean the scientific method. What they always seem to forget is that method is executed by humans. Imperfect, sometimes ego driven humans.
Possibly the most likely possibility?
1. It acts on the brain, one of the organs we understand the least.
2. It's relatively slow acting, and easy to miss in the early stages.
3. It impacts the older population which will have confounding health factors.
4. It doesn't fit neatly into a big category we already know a lot about, like infection or cancer.
The slow acting nature of it means also you have to wait a long time to see results of clinical trials; also because early stages are easy to miss that also means you are stuck studying people who are already pretty senile and thus might be beyond the point where you can make a big difference.
Ruxandra has a nice piece, focused on cancer, but the reasoning is basically the same here: biology is just really hard. Sometimes we get lucky but in general it's a long, slow slog.
[1] https://www.writingruxandrabio.com/p/why-havent-biologists-c...
Think of it like brushfire in an ecosystem, or species population imbalances leading to catastrophic breakdown. These are better understood in terms of system state and preconditions, as opposed to a trigger event.
Infectious disease, at least in the classic acute form (whether that's bacterial and fast - cholera - or viral and slow - HIV), is a more mechanistic process which can be halted by blocking a single step in its pathway.
Systems that remain healthy and balanced via dynamic processes are harder to reason about and fix, because the root cause of a disease state can be dozens of little things adding up to the system losing its ability to maintain homeostasis.
The research went awry in Alziemer's due to fraud but its being funded at a reasonable level, a level many with Long Covid or ME/CFS or Fibromylgia would be very happy to see but doubt will ever happen. Funding of diseases is not "fair", it isn't based on number of sufferers * quality life years lost and we should be spending more on medical research generally. Alzeimers is one of the better funded diseases in the world.
I'll probably be downvoted for this, but I honestly think quality of life of CFS is lower than Alzheimer's.
I truly wish that disease funding was based on science and metrics rather than marketing and vibes.
That being said, Alzheimer's absolutely deserves it's funding and it is very sad to see setbacks related to fraud.
That's also why Alzheimer's can take so long to develop. It's just one aspect that we've chosen to focus on because it's more clearly noticeable, but it cannot easily be treated in isolation from everything else. If it was, it would regress quickly without fixing the root causes.
Even the most unwell person (in the US) is still dragging themselves to the store and work, on average.
Simple, brief movement that we often relieve the elderly of is the pump that actions the lymphatic system.
Being older brings its own additions to the table.
When a topic only has a limited number of experts, those experts become gatekeepers.
Those gatekeepers directly or indirectly control research funding.
Gatekeepers necessarily harbor biases, some right and some wrong, about how the field should progress.
For Alzheimer's, some gatekeepers were conflicted and potentially directed the field in the wrong direction. Only time will reveal AB42's true role.
It's easy to find fault in Alzheimer's.
It's harder to see the general solution to the gatekeeper problem, i.e., how to allocate resources in areas with limited experts.
Perhaps funding like public grants could be controlled by few? Should not the case for private money?
Relatively common health issues older people tend to get fair amount of private funding after all.
Rich people tend to be older and they are lot more likely to see amongst their friends and family Alzheimer's and Parkison's or even cancer and so forth and be worried about it and thus donate money to them.
In somewhat related (i.e. old people health concerns) life extension research gets all kinds of wacky non traditional research lines get funded all the time, I don't understand why would Alzheimer's would be any different.
Generally, you rely on experts.
Who typically became experts by adhering to the conventional wisdom set by gatekeepers.
"Science advances one funeral at a time" feels apt.
Sadly, the problem isn't confined to Alzheimer's.
Whenever only a few people decide what is "right," the same pattern of stifled innovation will generally manifest itself not by design or from malice, but because it's hard for a small group to be 100% right on what works and what doesn't -- especially on matters as inscrutable as neuroimmune diseases.
While there are counter examples and inefficiencies in the system (and there are idea of addressing this, by distributing some part of the money in other ways), we have far bigger societal issues because people do not believe in science, especially where there is an industry lobby sowing doubts.
So I really want to push back against the the idea that the scientific system is broken. While there are real issues, this is still very misleading.
https://www.nature.com/articles/s41586-026-10407-9
(I’m an author)
The takeaway is to stop pretending that we can do good science when the ambiguity is so high, the majority of funding should go to people working on more concrete problems. We never locked in on vacuum tubes because the downsides were so obvious and the upsides of silicon transistors (if they could be made to work) were also obvious even to people outside the field, where your talent comes from. At the very least funders can't allow shifting goalposts, make them up front answer questions about the drugs. That will give you something to estimate the value of the drug and then when they come back with study after study outside the ranges they gave, you lower their funding. E.g. This is supposed to work on someone who was stage 2 and stop progression and then 5 years later it only "works" for stage 1 patients.
Strange breakthrough ideas can't even exist in the current system structurally, so going this route is the only logical choice. Which begs the question, why aren't clinical trials a private venture already? Governments are burning billions of taxpayer dollars for either nothing or cynically to keep the boomers alive and voting even longer, while 1/5 children are obese. For the rest of us we've socialized the risk and privatized the profits.
If you're looking to beat type-3 diabetes, you need to have a daily routine of exercise while you're young to keep these systems in shape when you're old.
You also don't need to belong to any marginalized groups, as ACEs tend to wear your body out over time -- breathing, kidneys, and heart in particular. People with traumatic childhoods (bullying, abusive parents, etc) have a huge risk of dying of dementia -- if their kidneys don't give out first.
Well, they seem to have some champions here...
I think you’re making a giant leap from A to Z and missing a whole bunch in between.
Stress ages the body. Homeless people can age several years, being on the streets for just a few months.
I've also seen numerous people in these upbringings die in their 50s and 60s from kidney failure. My stepdad was one of them. My father too.
My father had a normal childhood, except he had a traumatic experience of shooting his twin brother while they were playing cowboys and indians. Spent his entire life blaming himself. Went through all the normal development phases. Not on any meds.
His body just started shutting down prematurely. It's common in people with those experiences. First, his breathing got bad. Then his kidneys. Then he started having heart problems.
And that's the pattern. Heart, lungs, kidneys. Which are all linked to the brain. And eventually lead to dementia-like symptoms. At least that's what the research on ACEs seems to point out.
Marginalized people have a high death rate in their 50s and 60s, because of societal bullshit -- no other factors needed.
which is linked to nervous and endocrine dysfunction,
which is linked to Alzheimer’s/Dementia?
Meaning, failing of the glymphatic (and possibly lymphatic!) systems.
Unfortunately that insight hasn't led closer to a cure.
It also turns out sort of bad to tell people they have a horrible neurodegenerative disease 10 years before the major symptoms start.
Why isn't everyone's mind blown? Well for the cynical explanation, look at the state of science education and what people said about Artemis, vaccines, etc. or optimistically, there are too many mind blowing discoveries to treat them all fairly.
Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most guesses work to some degree to keep pharma alive - otherwise nobody would fund the business.
Edit: Google the in the pipeline blog. This and other have discussed this at length.
I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation.
[1] https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show".
Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
If anyone wants to know who wrote the article linked before wasting time reading it, there you go.
wrt. original post - quickly googled, and that for example https://www.news-medical.net/health/What-are-Amyloid-Plaques... - pretty short and seems to be clear that amyloids do have some correlation while may or may be not the cause.
"Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles"
Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this
https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20stud...
"The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. "
Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
It’s a miracle it works at all
Is that supposed to be an endorsement or a dismissal? The ostensible goals of "rationality" seem like good things, so it sounds like an endorsement, but in the wake of the FTX/SBF fallout they got a bad rap.
The people who know the most are probably busy and (not to be rude) are not necessarily the strongest educators.
Maybe my standard is too low here or I have a different need than you, would make a different accuracy-accessibility tradeoff…
I, also a non-expert, spent six months studying what the experts are doing, concluded that they actually seem to know what they’re talking about, and shared my understanding of that with other non-experts.
If you’re going to dismiss me for saying the experts are right, since I’m not an expert, then shouldn’t you dismiss those who spent far less time than I to learn about the subject, who are saying the experts are wrong?
Already have
> I thought despite the fraud, it's still the best model we have[1]?
It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines.
The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms.
So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender.
[1]: https://link.springer.com/article/10.1016/j.nurt.2008.05.004 [2]: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...
The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses.
It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise.
I fully agree with your point, though, just not the example.
The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
https://www.scientificamerican.com/article/exxon-knew-about-...
If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts.
The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world.
Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt.
It's all about money, power, and entitlement. Not about truth or responsibility.
But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.
“When we began our study, we felt that skeptics had raised legitimate issues, and we didn’t know what we’d find. Our results turned out to be close to those published by prior groups. We think that means that those groups had truly been very careful in their work, despite their inability to convince some skeptics of that.”
https://www.nas.org/blogs/article/after_climate_research_phy...
If you haven’t read up on both, it’s hard to appreciate how unlike climate science is from the beta amyloid theory. The latter has some evidence but there were always alternate theories by serious researchers because it involved multiple systems which scientists were still working to understand and basic questions around causation and correlation had significant debate.
In contrast, climate scientists reached consensus about climate change four decades ago and by now have established many separate lines of evidence which all support what has been the consensus position. More importantly, since the 1970s they have been making predictions which were subsequently upheld by measured data from multiple sources. The ongoing research is in fine-tuning predictions, estimating efficacy of proposed interventions, etc. but nobody is seriously questioning the basic idea.
Almost all of the people you hear dismissing climate change are funded by a handful of companies like Exxon, whose own internal research showing climate change was a significant threat produced a chart in 1982 which has proven accurate:
https://skepticalscience.com/pics/Exxonpredictions.png
https://insideclimatenews.org/news/16092015/exxons-own-resea...
...and it really did backfire (in public relations, politics, etc)
now... I don't think they can actually fund 'research-for-their-profit' -- I mean, would you believe "petro is good for earth" research coming from oil companies, even after the 'lead is good or neutral' research?
Not uncritically, but if the research presents a logically consistent hypothesis, and evidence supporting it, then it would be worth following up on with independent groups and if it remains consistent to scrutiny then it should be accepted.
That's how science works.
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc...
I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
Edit: I see you specifically pointed out "predictions of catastrophe", which if that is true (and not just the position of radicals on Twitter) is indeed unfortunate.
You didn't ask, but my opinion on it is that we'll probably stabilize on a cleaner energy source and find natural countermeasures when suffering ticks up. Any top down pressure to change things whole cloth seems doomed, no matter how benevolent. We're closed loop creatures.
What better way to find out than to just try it and see if we end up with runaway warming? That surely can't cause any harm.
Like are we doomed or will it just get a bit warmer before we switch to solar for example.
There are also money issues like with the alzheimer's situation. If climate change is dooming us then we should send more money to climate scientists.
Absolutely, the issues are similar
And if this can upend the business model of some big companies we'll give some "incentives" to some "doubtful" scientists even if their doubts are unfounded (actually very well founded but you get the gist)
Which sucks because such work should be free of pressures and incentives
Couldn't disagree more.
Please spend it on those who might actually fix something. There's plenty of can remove carbon or can undo the effect of X on Y. Let's stop falling back on the bad argument of we must leave nature alone right after arguing we change billion dollar industries because we can.
We shouldn't learn to be custodians watching the planet die because of past mistakes, we should be fixing and improving the planet and improving on nature because we can, must and should, shoulder this reaponsibility.
Please not _yet more modelling_ burning HPC into the ground just for a crappy bar line graph (based on assumptions)...
How do you do this without a process of finding out what works and what doesn't? Isn't that science? Or am I misunderstanding you saying no more modeling to mean we already know everything we might need to know in order to shoulder this planet scale responsibility and just collectively aren't doing anything except making bar charts?
What does your proposal actually look like without science or climate modeling?
There is a yawning abyss of states in between extinction and 'boy sure is a few degrees warmer out here' and none of them are good.
Many organisms would benefit from a warmer climate, just not humans.
We rely on extremely narrow conditions for the fragile supply chains and power structures that keep us on the ragged edge of civilized to continue working. We had an extremely mild contagious disease outbreak, by historic standards, and our economy is still feeling the effects!
Imagine the impacts of something like wildly different rainfall patterns, increased rate of global infectious disease, shifted agricultural zones, changes to Jetstream patterns, large scale crop failures, loss of water supplies, temporary local ecosystem collapses etc. These changes are incredibly fast on the scale of what it takes to reach ecological equilibrium.
These of course mean nothing to biological life, writ large. Life will recover and adapt. To fragile human civilization they mean refugee crisis, resource wars, failed infrastructure, and ten thousand other existentially terrible things.
and a whole fuckin lot that wouldn't, and that may collapse the ecosystem
Depends! If you're a large fossil fuel company, the obvious move might be to spend more money on advertising agencies scientists, or entire foundations who question climate science instead.
... which they did. https://link.springer.com/article/10.1007/s10584-013-1018-7
Meanwhile, the basics were known since the 19th century. https://www.rsc.org/images/Arrhenius1896_tcm18-173546.pdf
However research into what we humans can do to ameliorate it is verboten. For example https://www.scientificamerican.com/article/fertilizing-ocean... was an actual experiment that found a low cost way to both remove lots of CO2, and improve a fishery. But that line of research has been shut down.
Likewise research into the current impact is only allowed if it agrees with what is politically correct. For example many researchers have found that current severe California forest fires are mostly due to poor past policies, that have resulted in very dense forest, with a large fuel overload. But research that stresses the impact of climate change are easier to publish, and this shifts the apparent consensus on the causes of things like the major 2025 fires in the Los Angeles area.
> Not geoengineering
> The project is also unlikely to bury much if any carbon dioxide for one simple reason: metabolism. As other iron fertilization experiments have shown, it is relatively easy to get plankton to bloom, but it is harder for that bloom to sink to the bottom of the ocean, where it takes CO2 with it.
This project is a net carbon emitter by design.
The worst case scenario laid out in that article is that most of the carbon absorbed, was later rereleased. So net zero carbon, not net carbon emitter.
I've seen other reports of that exact experiment that estimated a significant net carbon sink. The actual experiment failed to make measurements that lets us know which actually happened.
Regardless, we've certainly demonstrated that, at least sometimes, there is significant net carbon capture, at low cost. Given the certainty of global damage at present, I believe that this justifies continued experimentation. Even if it means accepting possible risk to local ecosystems. The local ecosystem can generally recover. The planet, not so much.
With any position, you have to distinguish between its thoughtful advocates and its thoughtless ones-every position has both
Any thoughtful “climate change sceptic” is going to say (a) of course the climate is changing-it always has and always will; (b) of course it is implausible than human activity has literally zero impact on that change. But that still doesn’t tell us: (i) the relative scale of anthropogenic versus natural causal factors; (ii) the validity of any specific predictions of future change; (iii) the likely socioeconomic impacts of any future changes that may occur. It is totally possible that a person may affirm (a) and (b) while questioning the “consensus” on (i) and (ii) and (iii)
Personally, I don’t have a strong opinion on the substantive issue - but I wonder about the extent to which mainstream discourse on the topic represents good epistemic hygiene. It is even possible that the sceptics are on the whole more wrong than right, but simultaneously the mainstream response to them is more irrational than rational.
For Climate Change it's a question of opportunity costs. With expected inputs how much will temperature change? What are the effects of that change? How much effort to you put into changing the inputs? How much effort do you put into dealing with the effects?
The biggest difference is that Climate Change is a deeply political question with a bit of science tossed in. Alzheimer's is the mirror opposite - it's a scientific question with politics added to the same degree of most other things.
The idea that they have blocked the treatment of Alzheimer's rather than helping it, is very, very painful. This is perfect for creating cognitive dissonance.
And so, no matter what the evidence, they remain committed to the conclusion.
As a result, the latest Alzheimer's drug to enter stage 3 FDA trials is Trontinemab. (It is currently in stage 3.) It targets the amyloid target.
A relative drop in the bucket is going to, say, the infection hypothesis. This despite the fact that the only intervention that has been shown to reduce the incidence of Alzheimer's, is the shingles vaccine.
The financial motivation for fraud is all on the side of climate-change denial. Literally trillions of dollars of motivation.
Climate-change denial is just like tobacco-cancer denial. It's the same banal "I win, you all lose" mechanism. Enormous resources are available (along with the useful idiots) to propagate falsehoods.
The idea being both to make it easy to get people to agree today (the reductions are tomorrow's problem), and to allow time (and foresight) for industry to adapt to where things are going.
What happened is we got the tools to start studying viral associations with other diseases and ... whooops ... suddenly there are associations. The shingles and RSV vaccines seem to affect dementia while others like influenza don't.
Now people can ask questions about why those particular vaccines affect dementia while others don't. And suddenly we have falsifiable tests.
Now we can subject all hypotheses (including Amyloid) to stronger scrutiny.