The legacy of lies in Alzheimer's science

Professional advice and care are the best options but i think i can share some of our personal experience for what they are worth. I would say having a certain level of pragmatism is important without being insensitive with the person with this disease, for example one thing i wish we would have done earlier was to declare my father in law as "legally incapacitated", i am not sure what is the proper term in english but here in spain it means that they cannot legally bind themselves to anything without the consent of a tutor/guardian. This is a painful process because it takes time (judges, doctors, etc... must asses the case) and this acts as a constant reminder to the person with the disease of what is coming, making him/her feels useless. Another key aspect is being focused from the begining on what the healthcare system can provide for your relative as the disease progress, these bureucratic processes tend to be slow on my country, and since dementia progresses at different rates for each individual, it’s best to start looking into options early. Symptoms might advance rapidly in younger individuals.

Equally important is being sensitive and getting ready for what is to come, i don't think you can be optimistic so instead we focused on appreciating the time together, i started having more personal conversations with my father in law, we got closer and somehow that bond remains. We learned to be very patient because he went through a long period of aphasia, if he got stuck on certain phrases, we just gave him a bit of push completing the words he was missing. We also took long walks on nature. Being surrounded by a peaceful environment is important. As the disease advanced, he started to feel very confused, he couldn't recognize us sometimes and that made him angry, there was usually small hints before the outburst triggered, again being patient and trying to calm him down was important. Because he was relative young he was physically strong what was challenging but it is manageable, i think he needed to feel safe so focusing on that was a good strategy. Now he is not longer able to communicate, occasionally he says a few words and sometimes it can be even funny, it is fascinating how the brain still responds to humor even with dementia. When I sense he is nervous, I gently touch his back, and I can feel how much it reassures him. Support groups to share these experiences are important, take all the help you can get. When the disease reaches its final stages, seek the help of professionals. Their support can help the family maintain a sense of normalcy and be functional.

By the way, I just realized that I said it’s hard to be optimistic, but one thing I can truly say is that I value life so much more now. Every day that I wake up and feel present is a gift.

THANK YOU Pops died of Parkinson & Mum of Dementia.

My sole (selfish) aim on this matter being 500% certain my son be not burdened by my own demise. Brought a GOOD Lad into world I struggle to make sense of...

Consult:

https://www.youtube.com/watch?v=8QxIIz1yEsA

Thanks also for re-enforcing my silly notion that with few exception humanity are by nature GOOD, aside "Under Duress" ...

This is the sort of data (shove it under the rug) which profit-seeking 'studies' overlook. Inclusion could affect the bottom line, ya see.

Fossils (old folk) retired, what tax revenue do we generate?

It is terrifyin' being my age. A "dementia" diagnosis is very profitable to INSURANCE as in Medicare (EN-US) see?

Invitation for curious minds

Please AUDIT "treatment guidelines". Center for Medicare Services. FOLLOW THE MONEY

I close with HAY'LL NAW, n0t on our Watch. Should only myself stand alone, no problem at all... WE ARE NEVER ALONE

https://youtu.be/8QxIIz1yEsA

Counteradvice. Avoid seeking help from any kind of denominational spirit guides. Illusions do not relieve grief.

This - it's more like an end-stage failure mode of a self-regulating, dynamic system which has drifted into dysfunction.

A case of "lots of things have to work perfectly, or near enough, or a brain drifts into this state". This seems to be very much the case with cancers, essentially unless everything regulates properly, the system would on its own devolve into cancer.

Like a gyroscope which will only spin if balanced, only this gyroscope has 10^LARGE moving parts.

And when you consider the ageing process, you're talking about multiple systems operating at 50%, 75%, 85% effectiveness, all of which interact with one another, so it's inevitable that self-regulating mechanisms start to enter failure cascade.

In terms of interventions, a lot of the time it seems like the best fix is to look at which of the critical systems is most deteriorated, and try and bring that one up. So, for example, diet and exercise can restore a degraded circulatory system by a meaningful amount, but you can be an Ironman triathlete and still develop Alzheimers in your 60s. If we can find reliable ways to do the same for sleep, that will be worthwhile, and likely there are other systems where we might do the same - immune, liver, kidneys and so on.

Awesome clarification! Thank you.

We're not the researchers, we are developing the technology to support research. They are somewhat hamstrung with the currently available technology. There are other benefits to slow-wave enhancement, non-clinical and beyond dementia. It has been suspected this could play a role in prevention of AD, we were very suspicious (and still are a bit) that we could have a direct impact in treating AD.

Having said that, the paper that looked at people with AD saw improvement in sleep, so even if we can help them subjectively feel less exhausted, that could be a quality of life benefit, even if non-clinical.

I completely agree, that proving effectiveness in treatment is a long road, but we're going through a non-clinical use first. If the research works out, we can look into clinical use at a later date.

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It is actually and very unfortunately both.

One of the researchers we are connected to has posited that increased amyloid build up decreases the effectiveness of the glymphatic system, which is why we see lower delta power in older adults which then further reduces the ability to remove build-up. It's a vicious cycle.

We also see this with cortisol levels in under slept individuals and exacerbated in people with AD.

In response to a lack of sleep, the body increases cortisol, that increase in cortisol introduces challenges in getting good sleep, which increases cortisol.

For most of us, this isn't an issue as we get on top of our sleep within a fairly short period and sort this out, but in people with AD, there is a cortisol dysregulation, and potential a circadian issue as well.

One hypothesis why the AD paper I linked to earlier had such a huge impact on AD sufferers was because PTAS has been shown to have a 15% decrease in early night cortisol levels.

The cortisol levels were not checked in the AD subjects because it was a feasibility study, but I'll be speaking with the researchers next week, and hopefully that is the plan for the next stage research.

It's also hard to distinguish whether sleep disruptions cause AD or the other way around.

You are reading that correctly, however, it is likely a limitation of the technology they used in the study.

Strangely, the didn't mention how they decided on stimulation volume, however, most studies will either set a fixed volume for the study, or measure the users hearing while they are awake, and then set a fixed volume for that person.

Our technology (and we're not the first to do this) adapts the volume based on brain response during sleep in real-time.

When you don't do this you risk either having the volume so low that it doesn't evoke a response, or so high that you decrease sleep depth, and don't get the correct response.

Therefore, anyone who did not get the appropriate volume would end up as a non-responder.

It is also more challenging for previously used algorithms to detect a slow-wave in older adults because the delta power is lower, so some of these participants may have had limited stimulation opportunities.

We've developed methods which improve on the state of the art, but we have not validated those in a study yet.

Certainly pop-sci but great on this topic:

https://www.waterstones.com/book/why-we-sleep/matthew-walker...

I'm not as optimistic as you that sleep will be a cure, but I'd be very surprised indeed if sleep quality weren't preventive. (Proving this might be more difficult, though - correlation/causation).

It's almost an argument by process of elimination - why else would literally every living thing with a brain need to spend so much of its time asleep? How is it that we still don't fully know what sleep (as distinct from either rest or unconsciousness) is actually for?

Multiple studies show that night shift work is bad for the brain - and for those with a habit of working nights (probably quite a few of us on HN, from time to time), if a recreational drug made your brain feel as bad as an all-nighter can, that would surely be one you'd put in the "treat with great caution" category, no?

No doubt the glymphatic system (a central part of higher animal physiology which was only discovered in the last 25 years) has a role to play. It may be that, as with cancer, once the degenerative process gets beyond a certain point, it's hard to stop - but I'm hopeful that science will unlock a good deal of understanding around prevention over the next decade or so - even if that's not much more than an approach to sleep hygiene analogous to "eat your 5 fruit and veg a day, don't have too much alcohol or HFCS, and make sure to do a couple of sessions of cardio and a few weights every week".

> The current system lies on the market of ideas - ie if you publish rubbish a competitor lab will call you out.

Does not happen in practice. Unless you're driven by spite, fanaticism towards rigorousness, or just hate their guts there is zero incentive to call out someone's work. Note that very little of what is published is obvious nonsense. But a lot has issues like "these energy measurements are ten times lower than what I can get, how on earth did they get that?" Maybe they couldn't or maybe you misunderstood and need to be more careful when replicating? Are you going to spend months verifying that some measurements in a five-year-old paper are implausible or do you have better things to do?

How is that correction mechanism supposed to work though? Do you mean the peer review process?

Friends in big labs tell me they often find issues with competitor lab papers, not necessarily nefarious but like “ah no they missed thing x here so their conclusion is incorrect”.. but the effect of that is just they discard the paper in question.

In other words: the labs I’m aware of filter papers themselves on the “inbound” path in journal clubs, creating a vetted stream of papers they trust or find interesting for themselves.. but that doesn’t provide any immediate signal to anyone else about the quality of the papers

I'm in academia, and I think it has many good points.

The number one issue in my mind is competitors labs don't call you out. It's extremely unusual for people to say, publicly, "that research was bad". Only in the event of the most extreme misconduct to people get called out, rather than just shody work.

Yeah I don't think CRM is the correct thing in this case... I just think that there needs to be some new set of incentives put in place such that the culture reinforces the outcomes you want.

Project managers and consultants do actually write those documents/specifications justifying the work before the programmers get to do it.

How else would it work? The onus needs to be on someone to make sure we are doing worthwhile things. Like anything else in life, you need to prove you deserve the money before you get it. Often that means you need to refine your ideas and pitches to match what the world thinks it needs. Then once you get a track record it lowers your risk profile and money comes more easily.

Imagine if everybody in every software company was an "engineer," including the executives, salespeople, and market researchers. Imagine if they only ever hired people trained as software engineers, and only hired them into software development roles, and staffed every other position in the company from engineering hires who had skill and interest at performing other roles. That's how medical practices, law firms, and some other professions work.

For example -- my wife is an architect, so I'm aware of specific examples here -- there are many architecture firms that have partners whose role consists of bringing in big clients and managing relationships with them. They are never called "sales executives" or "client relationship management specialists." If you meet one at a party, they'll tell you they're an architect.

Apparently it's the same thing with scientific research. When a lab gets big enough, people start to specialize, but they don't get different titles. If you work at an arts nonprofit writing grant applications, they will call you a grant writer, but a scientist is always a scientist or a "researcher" even if all they do is write grant applications.

> Imagine if programmers spent 40% of their time writing documents asking for money to write code.

The daily I'm not taking part anymore at work started today at 9:30 as always, and has currently (11:50) people excusing themselves because they have other meetings...

We need a revolution on exposing bad managers and making sure they lose their jobs. For every kind of manager. But that situation isn't very far from normal.

Unfortunately as you spend more time investigating this problem it becomes clear that replication studies aren't the answer. They're a bandage over the bleeding but don't address the root causes, and would have nearly no impact even if funded at a much larger scale. Because this suggestion comes up in every single HN thread about scientific fraud I eventually wrote an essay on why this is the case:

https://blog.plan99.net/replication-studies-cant-fix-science...

(press escape to dismiss the banner). If you're really interested in the topic please read it but here's a brief summary:

• Replication studies don't solve many of the most common types of scientific fraud. Instead, you just end up replicating the fraud itself. This is usually because the methodology is bad, but if you try to fix the methodology to be scientific the original authors just claim you didn't do a genuine replication.

• Many papers can't be replicated by design because the methodology either isn't actually described at all, or doesn't follow logically from the hypothesis. Any attempt would immediately fail after the first five minutes of reading the paper because you wouldn't know what to do. It's not clear what happens to the money if someone gets funded to replicate such a paper. Today it's not a problem because replicators choose which papers to replicate themselves, it's not a systematic requirement.

• The idea implicitly assumes that very few researchers are corrupt thus the replicators are unlikely to also be. This isn't the case because replication failures are often due to field-wide problems, meaning replications will be done by the same insiders who benefit from the status quo and who signed off on the bad papers in the first place. This isn't an issue today because the only people who do replication studies are genuinely interested in whether the claims are true, it's not just a procedural way to get grant monies.

• Many papers aren't worth replicating because they make trivial claims. If you punish non-replication without fixing the other incentive problems, you'll just pour accelerant on the problem of academics making obvious claims (e.g. the average man would like to be more muscular), and that just replaces one trust destroying problem with another.

Replication failure is a symptom not a cause. The cause is systematically bad incentives.

That's a tremendously expensive way to detect fraud. There's funding, but also the people replicating need to have at least near the expertise of the original authors, and the rate of false positives is clearly going to be high. Mistakes on the part of the replicator will look the same as scientific fraud. Maybe most worryingly, the negative impact of human studies would be doubled. More than doubled, probably- look at how many people claimed to successfully replicate LK-99. A paper may need to be replicated many time to identify unknown.

Maybe first we could just try specifically looking for fraud? Like recording data with 3rd parties (ensuring that falsified data will at least be recorded suspiciously), or a body that looks for fabricated data or photoshopped figures?

> Right now, it often takes decades to uncover fraud.

Where? Many in this thread are talking as if there is monoculture in academia.

See, for example, a paper mill that churned out 400 papers with potentially fabricated images: https://www.science.org/content/article/single-paper-mill-ap...

Influential microbiologist Didier Raoult had 7 papers retracted in 2024 due to faking the ethics approvals on the research. https://www.science.org/content/article/failure-every-level-...

Fazlul Sarkar, a cancer researcher at Wayne State University, had 40 articles retracted after evidence of falsified data and manipulated and duplicated images. https://www.liebertpub.com/doi/10.1089/genbio.2024.29132.ebi

Overall, Elisabeth Bik has found thousands of studies that appear to have doctored images. https://www.newyorker.com/science/elements/how-a-sharp-eyed-...

Are you saying publications need a bug bounty?

From what I've read, those drugs are very good at removing amyloid, but despite that, they don't seem to make much of a noticeable (clinically meaningful) difference in the people treated with them. I personally would not call that a "huge success".

After many decades of research, we've gone in the last few years from no ability whatsoever to affect the underlying disease, to 30% slowdown. To be clear, that's a 30% slowdown in clinical, cognitive endpoints. Whether you call that "meaningful" is a bit subjective (I think most patients would consider another couple years of coherent thinking to be meaningful), and it has to be weighed against the costs and risks, and there's certainly much work to be done. But it's a huge start.

If they are so good at cleaning up the amyloid, why don't people have more of an improvement?

No one is expected to improve after neurodegeneration has occurred. The best we hope for is to prevent further damage. Amyloid is an initiating causal agent in the disease process, but the disease process includes other pathologies besides amyloid. So far, the amyloid therapies which very successfully engage their target have not yet been tested in the preclinical phase before the amyloid pathology initiates further, downstream disease processes. This is the most likely reason we've seen only ~30% clinical efficacy so far. I expect much more efficacy in the years to come as amyloid therapies are refined and tested at earlier phases. (I also think other targets are promising therapeutic targets; this isn't an argument against testing them.)

I think everyone agrees amyloid is associated with Alzheimer's, the question is how much of a causative role does it play.

To be clear, the evidence for the amyloid hypothesis is causal. The association between amyloid and Alzheimer's has been known since Alois Alzheimer discovered the disease in 1906. The causal evidence came in the 1990's, which is why the scientific community waited so long to adopt that hypothesis.

>If they are so good at cleaning up the amyloid, why don't people have more of an improvement?

I have zero knowledge in this field, but there's a very plausible explanation that I think is best demonstrated by analogy:

If you shoot a bunch of bullets into a computer, and then remove the bullets, will the computer be good as new?

“Amyloid is going to be — has to be — a part of the Alzheimer’s story, but it is not, cannot be a simple ‘Amyloid causes Alzheimer’s, stop the amyloid and stop the disease,'”

It's not quite that simple, and the amyloid hypothesis doesn't claim it to be. It does, however, claim that it's the upstream cause of the disease, and if you stop it early enough, you stop the disease. But once you're already experiencing symptoms, there are other problem which clearing out the amyloid alone won't stop.

What’s more, lecanemab only improved scores by 0.45 points on an 18-point scale assessing patients’ abilities to think, remember, and perform daily tasks.

As I point out in another comment, the decline (from a baseline of ~3 points worse than a perfect score) during those 18 months is only 1.66 points in the placebo group, It's therefore very misleading to say this is an 18-point scale, so a 0.45 point benefit isn't clinically meaningful. A miracle drug with 100% efficacy would only achieve a 1.66 point slowdown.

To be clear, I think you're asking whether maybe the drugs just provide a temporary "lift" but then the disease continues on the same basic trajectory, just offset a bit?

The studies aren't statistically powered to know for sure, but on lecanemab figure 2, the between-group difference on CDS-SB, ADAS-Cog14, ADCOMS, and ADCS-MCI-ADL (the four cognitive endpoints) widens on each successive visit. Furthermore, while not a true RCT, the lecanemab-control gap also widens up to 3 years in an observational study: https://www.alzforum.org/news/conference-coverage/leqembi-ca...

On donanemab figure 2, there is generally the same pattern although also some tightening towards the end on some endpoints. This could be due to the development of antidrug antibodies, which occurs in 90% of those treated with donanemab; or it could be statistical noise; or it could be due to your hypothesis.

https://www.reddit.com/r/medicine/comments/1057sjo fda_oks_lecanemab_for_alzheimers_disease/

"Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities *with edema or effusions in 12.6%*."

https://en.wikipedia.org/wiki/Cerebral_edema

"After 18 months of treatment, lecanemab slowed cognitive decline by 27% compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs 1.66 with placebo; P < .001)"

https://www.understandingalzheimersdisease.com/-/media/Files...

Sum of boxes is a 19 point scale. So, for those keeping track at home, this is an incredibly expensive treatment that requires premedication with other drugs to control side affects as well as continuous MRIs for an ~%2.3 absolute reduction in the progression of dementia symptoms compared to placebo, with a 12% risk of cerebral edema.

Now, I'm no neurologist, but I'd call that pretty uninspiring for an FDA-approved treatment.

> Downvoters, are you sure you have a rational basis for downvoting this informative post?

Citing relative improvement (30%) instead of absolute improvement (2%) and not explicitly designating it as such.

I did not downvote, but OP failed to provide a link to back up his claim, or to make explicit what "slowing decline by about 30%" even means.

In light of the fraudulent and scandalous approval of aducanumab [0] (which also targeted amyloid), such claims must be thoroughly referenced.

[0] https://en.wikipedia.org/wiki/Aducanumab#Efficacy

How do you know what the downvote status is?

Billions have been spent because it's a challenging disease to understand and treat. I want big progress too. But we shouldn't let our desire for big progress cause us to lose our ability to objectively evaluate evidence.

I have no opposition to a properly controlled randomized controlled trial of the keto diet, or other proposed therapies (many of which have been conducted, and are for targets other than amyloid which are completely compatible with the amyloid hypothesis). Until a proper RCT of keto is conducted, anecdotal claims are worth very little compared to the evidence I referred to.

There are also studies showing a plant-based diet can reverse Alzheimer's symptoms as well. It has to do with atherosclerosis.

Why do employees keep voluntarily accepting that type of abuse? Low wages aren't a secret and the employees doing that work aren't idiots so they must know what they're getting into. Are they doing it out of some sort of moral duty, or as immigrants seeking permanent resident status, or is there some other reason? Presumably if people stopped accepting those wages then the wages would have to rise.

You keep bringing up one state in the union as if the whole system is flawed because of this one state.

curious if you could link to relevant papers? Thanks!

I agree with you that OPs ideas don't work. But I don't agree with you either. Let me point to a far more fundamental problem which is that even your well meaning lab is still a ponzi scheme that survives only because it gets cheap labor in the name of more trainees when there's no evidence that the academic system can handle MORE people. Even if we have the funding, the peer review systems we are dependent on are clearly becoming less effective just because of pure volume and breadth.

I have other issues with the system but in the end this is the most important problem I see to be solved first.

at this moment, what NIH? No study sections for grants since the inauguration...

They are joking.

I also can't tell whether Stanford is joking, but the notion that he's a good fit for the job of biology professor is definitely funny!

There are betrayals so severe that a grindingly slow due process is actually itself an addition betrayal. Not arguing for a kangaroo court, but tenure should not be a defense for blatant cheating.