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...
>> 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.
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.
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.
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.
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.
> 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.)
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.
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 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.
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.
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.
> 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.
Readit News
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.
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.
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...
> 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.
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
> 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.
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.
As for other treatments, medicine basically boils down to surgery, drugs, and/or letting your body heal itself. The latter clearly doesn't work and for progressive diseases surgery generally isn't effective, so you're back to drugs.
Getting diagnosis and treatment for vitamin defficiency, hormonal imbalance, stomach microbiome, psycology related issues, and many other conditions simply does not happen unless patient does his own reading and pesters the doctor for treatment.
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.
Deleted Comment
(1) Pathological levels of amyloid-beta and tau are present in cognitively normal individuals, and
(2) some individuals clinically diagnosed with AD do not have amyloid-beta pathology.
> Or maybe the real problem is the excess emphasis on finding a drug in specific that can be commercially monetized. A single drug for a single cause of what is likely a complex process.
And the proceeded to write this:
> Amyloid and another protein (tau) accumulate in the brain due to sleep deprivation. Helping people get a good night's sleep -- without drugs -- would likely help
And didn't see the irony at all?
isn't it still just a hypothesis that long term sleep deficits could be connected to dementia?
https://news.ycombinator.com/item?id=25427090
Or reverse causation.
Dead Comment
> 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.
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.
~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.)
Normally there's excitement when the research offers some weird or novel tie in or a better way of doing a thing or solving a problem.
But then again these fields don't have the same structure of paymaster.
what agencies are more free from politicians manipulating their funding? (this sounds hopeful)
We judge ourselves by our intentions.
We judge others by their actions.
This leads to people with evil actions judging themselves as good. “I didn’t want to do it. They gave me no choice.”
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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.
If it turns out to be an infection, their whole career has been a waste. Can they even find something to do, then?
Basically, don't blindly trust science, because science isn't just some imagined ideal of objective research. It is fund raising, reputation, ladder climbing, ego, dogma, etc...
People believe all sorts of idiotic things with utter confidence, then act on those beliefs to the detriment of others.
Many of the worst things to happen in the past few decades happened because of ignorant hubris.
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Derek Lowe: Had Enough, Eh? Come Back and Take What's Coming to You! https://www.science.org/content/blog-post/had-enough-eh
>It is hard to even begin to estimate the amount of time, effort, and money that has been spent on this idea. And this is just the antibodies! There are plenty of other whacks that have been taken at the amyloid hypothesis (secretase enzymes and more), and none of them have ever worked. Keep in mind that there are plenty of preclinical efforts over the past thirty years that never even saw the light of day (I was on some of those myself), and the reason you never heard about any of them is because they didn't work, either. Nothing has worked. Not once. The amyloid hypothesis has been targeted again and again and again from different directions with different drug candidates, and never, ever even once has it shown signs of truly helping Alzheimer's patients. I very much include Biogen's Aduhelm in that assessment. So I ask again: how long are we going to keep doing this?
Some quotes from their letter:
> Taken together, the preponderance of evidence argues that using the diagnosis of ASD in research is fruitless because the diagnosis is an arbitrary unscientific “convenient fiction” that has blocked the discovery of replicable neurobiological variation among individuals with serious neurodevelopmental social impairment.
> More than seventy years of research studying the arbitrary diagnosis of autism has not resulted in any targeted medical treatments. Now is the time to abandon the ASD diagnosis in research.
https://doi.org/10.1002/aur.1832
And, somebody always pops up self-righteously insisting Gold Standard Randomized Controlled Trials prove that none of the medications that millions of people need daily to be able function at all have any effect.
Discontent with the DSM is very widespread, in significant subsections of both research and clinical communities – however, attempts to dethrone it in practice are met with opposition from that other current of professional opinion ("it obviously is far from perfect but we need something and nobody's convinced us there is anything better"), and that other current seems to thus far be winning in the money/power/mindshare stakes.
> The wastebasket diagnosis means that no new medication can be found to have any useful effect, because it only treats a small fraction of patients in a trial, and worsens others.
New pharmacotherapies for depressive disorders do get approved – in 2019, the FDA approved brexanolone for post-partum depression and esketamine for treatment-resistant depression; before that, the FDA approved vortioxetine in 2013. Agometaline was approved in the EU in 2009 and and Australia in 2010, although its manufacturer gave up trying to get it approved by the FDA. And there are further new drugs in various stages of the approval pipeline. Brexanolone is particularly interesting as a drug to treat a rather specific form of depression rather than just "vanilla depression".
No denying it could be better, but depression is a much better situation than autism/ASD – although risperidone and aripiprazole are both approved to treat behavioural issues (irritability and aggression) in children with ASD, neither has any impact on core autistic traits (social cognition, obsessiveness, etc). At least for depressive disorders, we have approved pharmacotherapies to treat their core symptoms, even if they only work for some patients some of the time.
autism probably covers hundreds of discrete genetic disorders that share similar pathology. for instance, Rett syndrome is sometimes considered part of ASD, but only explains a small number of ASD diagnoses.
I don't think that precludes ASD from being a useful diagnostic category, though. behavioral therapists don't need to know your genotype to help you cope with sensory overload. schizophrenia probably works the same way, but you still prescribe antipsychotics regardless.
It is possible to have "sensory overload" – even severe problems with it – yet not have enough of the other symptoms of ASD to meet its diagnostic criteria. How do behavioural therapists treat sensory overload in a person without ASD? Pretty much in the same way that they treat sensory overload in people with ASD! Conversely, it is possible to meet the ASD diagnostic criteria, and yet have no sensory issues needing treatment – such people exist too.
That's the thing – received wisdom justifies the clinical use of diagnoses as useful in treatment planning - but if you subject that received wisdom to scrutiny (too rarely done), it doesn't hold up very well. Almost all treatments in psychology/psychiatry/etc are (at best) symptom-specific not diagnosis-specific – almost all symptoms occur in multiple diagnoses, and many diagnoses have no one essential symptom. If person A has diagnosis B with symptom C – their treatment for symptom C will often be very similar, even identical, to the treatment of that same symptom in some other person who has completely different diagnoses instead.
> schizophrenia probably works the same way, but you still prescribe antipsychotics regardless
The same point applies to medications – medications don't really treat disorders, they treat symptoms. Antipsychotics are used to treat psychosis – which is a symptom which occurs not only in schizophrenia spectrum disorders, but very commonly seen in mood disorders as well (bipolar disorder with psychotic features, depressive psychosis), and (less commonly) can occur as a symptom of many more. Yet, whatever their diagnosis may be, a person with psychotic symptoms is highly likely to be prescribed an antipsychotic.
Added to that, you can also be prescribed an antipsychotic without having any psychotic symptoms, since various antipsychotics are FDA-approved for treating non-psychotic conditions, including anxiety, behavioural issues in children with autism/ASD, bipolar disorder, depression and Tourette's syndrome, along with various non-specific symptoms such as "agitation", "behavioural problems" (ADHD, ODD, DMDD, conduct disorder, personality disorders), and "hyperactivity" [0] – to say nothing of their very widespread off-label use.
[0] https://www.ncbi.nlm.nih.gov/books/NBK84656/
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.
(1) Pathological levels of amyloid-beta and tau are present in cognitively normal individuals.
(2) Some individuals clinically diagnosed with AD do not have amyloid-beta pathology
(3) spatial appearance, progression and absolute amount of amyloid plaques does not correlate with declining cognition more conclusively than other pathologies.
(4) It's not even clear that that amyloid-beta pathology is the first AD biomarker. Not even among those with APP, PSEN1 and PSEN2 biomarkers.
(5) it looks like autosomal dominant AD may be a different disease than sporadic AD and results there don't apply.
(2) Amyloid plaques are not the only thing that causes dementia. However genuine AD diagnoses are confirmed post mortem via autopsy and are typically assigned a BRAAK score (most large scale studies require plaque confirmation for cohort inclusion; i.e. AD definitionally requires amyloid presence).
(3) From the large datasets I've worked with, BRAAK score and AD age of onset are HIGHLY correlated. I'm genuinely curious to hear what biomarkers are more correlated.
(4) What is clear-er?
(5) Agree LOAD and EOAD are not identical diseases.
However, if another outcome of that interaction were found, then the "amyloid cascade hypothesis" would be easier to reject.
Recent work by several independent groups has focused on disruptions to the endolysosomal system as an alternative causative mechanism, e.g. Lee et al, 2022, discussed in the link below. One should note that despite the claim in the title, the authors may actually finger APP-C99 as causative in the original paper, which I have read very carefully (or rather fail to distinguish between Abeta and APP-C99).
https://www.alzforum.org/news/research-news/behold-panthos-t...
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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919248/
A larger trial (n=130) is expected to complete by December 2023 (it was originally expected to complete around now, but just finished recruiting):
https://beta.clinicaltrials.gov/study/NCT03282916?patient=NC...
Got my Tdap, too, because a colossal US Veterans Administration study showed that a recent Tdap booster predicted a 40% reduction in dementia risk. Dunno anything else with that predictive power.
For a field with no real results to have "superstars" is a sign of corruption.