"Scientists researching possible candidates for treating Alzheimer's disease found exercise outperformed all tested drugs for the ability to reverse dysregulated gene expression."
https://www.nature.com/articles/s41598-022-22179-z
Modern medical tech and practices are keeping us alive healthier and longer. Being disheartened by the fact you still need to eat right, sleep, etc. is like being disheartened that you still need to do regular maintenance on your car and treat it well.
The simple fact is that if you sabotage your body, you'll have more issues cropping up sooner and with greater severity, and if you keep it strong all that medical advancement actually has an opportunity to help you in the cases where your body can't help itself. It doesn't discredit medical advancement, only reminds us that many people's lifestyles can often be more destructive than we realize.
The thing with eating and sleeping right etc is that we know the limits of it: it can keep you alive into your 90's at best, and more realistically into your 80's. Technology on the other hand is completely uncapped. A pill that keeps a degenerate bum alive into the 80's might be really hard to achieve, but the kicker is that once you do, it's just another step or two to keeping him alive until 200.
Isn’t genetics more important? There are families where everyone dies young - look at the guy who popularized jogging. All the men in his family die young. He tried to beat it be exercising, eating healthy, etc. Still died young. Same age as his father.
Others families live into their hundreds without any effort. It would seem the first thing to do is to figure out a way to fix DNA.
In 1986 exercise physiologist Kenneth Cooper published an inventory of the risk factors that might have contributed to Fixx's death.[6] Granted access to his medical records and autopsy, and after interviewing his friends and family, Cooper concluded that Fixx was genetically predisposed—his father died of a heart attack at 43 after a previous one at 35,[7] and Fixx himself had a congenitally enlarged heart—and had an unhealthy life: Fixx was a heavy smoker before beginning running at age 36, had a stressful occupation, had undergone a second divorce, and gained weight up to 214 pounds (97 kg).[8] Medical opinion continues to uphold the link between moderate exercise and longevity.[9]
Not to state the obvious, but old people are really, well, old (and frail).
Your pill would need to do a lot of heavy lifting. I'm no doctor, but your pill would need to deal with mental issues (dementia of all kinds etc) and physical issues, like muscle mass, bone density, flexibility, skin elasticity and lots more.
There are very few, dare I say no, 90 year old that could pass for 70 - what sort of condition would 120 bring? Or 130 etc?
As an expert in one field, used to customers waving their hands telling me "this won't take long for you to do, it's very simple", I feel like your belief in (medical) technology, and what is possible, may be just a touch optimistic.
Presumably some sort of cellular rejuvenation - perhaps a way of gradually replacing senescent cells with healthy cells and/or of activating telomerase without causing cancer - would have beneficial effects across your entire body.
There are already large mammals - bowhead whales - that can live 200 years. Perhaps we can adopt some of their longevity traits without having to become giant ocean creatures.
Quality of life is a thing that a bunch of people miss though. If you're active in your middle ages then you're going to be able to do so much more as an 80 year old. You can also play it risky and be super shitty to your body in your 40s because you can afford to but then the next 40 years will suck. And doctors won't let you just die. They'll keep you alive as long as possible. Staying alive isn't the hard part.
Or taking the car example in another direction, it's like being disheartened that you can't put diesel in your car that takes regular unleaded gasoline
We need the proper fuel, substrates, and cofactors to operate well and not do unnecessary damage
>I hate this because I want to believe technology and AI and will result in modern medicine where everyone has long healthy lives.
Medical technology and AI is not even close to any major improvement in life expectancy, except in much rare cases (heart transplants is one example: they're insignificant in raising overall life expectancy, as they're statistically too rare to matter).
The big majority of the improvement in life expectancy in the 20th century was from low-hanging stuff like running water, sterilization, waste disposal, and basic antibiotics, not from the high-tech transplants, DNA research, fancy drugs and so on.
Fancy drugs save lives. Big time. My Mom had cancer and was treated with Rituximab. She's doing just fine 10 years later. That type of cancer would have been a death sentence 30 years before. There are lots of other anti-cancer drugs like Rituximab, and they save lives every day.
Despite these advances, life expectancy in the US is declining. If you google for something like ‘life expectancy change if cancer cured’ you’ll find that estimates of the effect on life expectancy of curing heart disease and cancer don’t exceed more than several years each. And looking into the far future, even if all disease is cured, and aging eliminated, life expectancy only increases to around 1000.
Wanna keep it from turning murderbot or paperclip maximizer? Welcome to the arena of politics of correct values. Wanna use it for longevity research? Same.
Some people also would like to make sure it isn't helping stoke antisemitism or genocide, but apparently that's controversial for some reason, so guess it's political.
(And that's before we get to the usual issue that people using "politically correct" as the drive-by aspersion that's so unfortunately common are usually more ideological than those they criticize and very much have their own political correctness they're anxious to impose by any means available to them...)
Having been vaccinated for Tdap recently very reliably predicts a 40% lower risk of dementia.
I gather flu vaccine has similar effect size. Nobody knows why. Ask, and people speculate about inflammation.
Having been treated for herpes lately -- valacyclovir, lately -- seems too to have outsize effect. I get all three.
People doing autopsies say brains they examine are very often laced with herpes virus and bacteria, vs. doctrine that insists nothing gets in.
US grants $2B annually to study plaque formation in transgenic mice. Approximately none of it goes for anything of value. When the amyloid boat sinks, a lot of biochemists will need to find something else to do. They would better look early.
I'm young (early 30s) but have a strong family history of late onset Alzheimers (my father, and both of my mother's parents).
I also get cold sores on occasion. I've brought this -- and the HSV-Alzheimers connection -- up to my doctor and a nurse, but neither had heard of the connection before (but I directed them to [0]), or thought it was worth pursuing anything like valacyclovir.
Roughly, the sentiment was that I am young and have time to wait for more research, that taking drugs long term will itself likely have consequences.
I'm not inclined to disagree there, although the evidence seems quite strong.
I look forward to seeing more funding and scientific effort directed toward other avenues.
> Says the guy hypocritically from his smartphone.
How is it hypocritical? Opposed to any other times in human history you can’t give up on society and live a peaceful life in a community.
We’re born into it along with all our families and friends. Telling someone to go off and live in the woods is a life of solitude and probably harsh run ins with the law.
There is no choice nowadays and saying “ha but you live in society so you can’t critique it” is a willful ignorance.
Seriously, if you really believe you're better off without technology, you can live that way without going and living in the woods. Saying you're better off without technology from a smartphone is hypocrisy. I double down on that.
Because the Amish are a Christian organization that’s been around for over a hundred years.
Also, you still have to give up all your family and friends and live by strict Christian values. Not everyone’s cup of tea, especially if one happens to be different in some way.
Sure, but I'm not recommending anyone join the Amish, just pointing out it is possible to live without a lot of technological informed in your life if you truly believe you'd be better off that way. It would be extremely dumb, but it's possible.
That's not a realistic view though. Technology and AI aren't some magical things that remove the need to have a balanced life. At the end of the day, we are living/breathing animals that depend on the things around us to grow and thrive.
On the other hand it makes so much sense. We're the result of hundreds of millions of evolution on this planet, and we're very optimized for the actions that we can take in nature (e.g. Walk, swim, hunt an animal/grap a fruit, eat, reproduce).
No wonder why these are good for us, because these are our true traits.
Modern medicine, on the other hand, is a few hundred years old at best and generally work as a band-aid rather than solving the root of the problems.
Exercise always seems counterintuitive. After all, things tend to wear out and break when you use them. You don't use the good scissors for most things or they won't be good when you need them. We would be a lot less grumpy if the way to build muscle was to take it easy, and you only needed to exercise if you were overbulking and needed to wear some out. So we want a pill that triggers the regenerative effects of exercise without the actual exercise. Human Growth Hormone without the problems.
Evolution doesn't care if you're grumpy, it only "cares" if you succeeded in reproducing.
Tissues that aren't stressed naturally atrophy to conserve energy, which saves on food, which is adaptive in evolutionary terms. This has the natural implication that those tissues will reach an equilibrium where they are barely stronger than your most basic needs.
If the only stress you experience is getting off the couch to get some food, just doing that will be a little difficult. Larger, sudden stresses will cause injuries because your tissues won't be adapted to handle them.
Exercise ensures that we mentally and physically exceed our normal stress thresholds, so the remaining stresses of life is less stressful by comparison.
Our body is breaking down constantly, but it's also rebuilding itself. It's not an inanimate object which wears down until it breaks.
I view exercise as giving your body, and brain, proof that the rebuilding is still needed, and information on where to direct resources.
If you never take a walk, why expect your body to rebuild itself to be good at walking? Eventually it'll lose its capacity because it (correctly) "learns" that isn't important to you.
I really enjoyed the book "Move your DNA". It talks a lot about the loads you place on your body (even ones you don't think about) and the effects that has. Definitely worth a read.
That should be encouraging, not disheartening. The best methods for keeping healthy just involve easy simple things anyone could do for free everyday. That’s better than any dependence on shitty expensive drugs.
Waaay easier than external AI and technology interventions, which don't even fully exist yet and without side effects.
I mean, think of it as bodybuilding: there are plenty of good ol' ways of building strength and stimulating hypertrophy on purely natural processes, and that shouldn't be disheartening as compared to, say, injecting yourself with steroids.
Humans are a very long lived species already at least when compared to most other large high metabolism mammals. That means evolution already did a lot of optimization for longevity, possibly driven by the high value of grandparents in child rearing and passing on valuable knowledge.
This is also why lots of mouse longevity research doesn’t translate well to humans. Mice are not a particularly longevity optimized mammal so it means there is more low hanging fruit there.
For us all the low hanging fruit is likely picked.
I wish gyms were less expensive, and had places, even a table perhaps, that kids and tweens could use. It would make exercise more accessible for me and my lifestyle.
In university, I had an indoor track I could use, it was fantastic and had plenty of room for families and people exercising.
No, we need cities and towns that are designed around active transport. Exercise should not be a "thing you do", it should just be part of life. If you want to "do exercise" it needs to be in addition to the normal every day base level of exercise everyone gets for free.
That said, you don't need to wait to be given those opportunities. Look for every opportunity for unnecessary expenditure of energy - you'll find there are plenty.
This. When I lived in Europe I was getting 60+ minutes of walking every day just between work and home and lunch and work. In Korea, I get 40+ minutes to and from subway stations. Family in the US will tell me they went for a really good 30 minute walk, and the thought I'm too polite to express is "How is 30 minutes of walking special enough to tell me about?"
Basically Singapore. Unfortunately that country can't be model in any western countries due Chinese inherent concept of devine right to rule (mandate from heaven). The system depends on people believing in a single party in overwhelming majority (>65%) and mandatory voting. Western countries depends on majority of voters being lazy and bot involved and let a small subset of vocal minority to control the government with small margin of winning votes (~55% out of say 60% voters turnout). For a city to be designed around active lifestyle, you need strong and consistent government with good resources to implement. Even some Nordic countries that are well ran compare to say a messy western country like USA, still can't implement the active lifestyle properly and consistently across more than a single election.
This should be in every city. The only way I could reliably exercise when my kids were babies was by running them in a stroller.
Apart from the mental health aspect (lack of agency, no time or space to yourself), you can’t always subject your kids to the weather of the day or they’re uncooperative to the point that the run isn’t feasible. Not to mention the multitude of reasons people can’t run, from disabilities to simply having no safe place to run with a stroller. Smooth sidewalks with space are kind of a luxury.
With a lifestyle and/or restrictions like that, no wonder people get out of shape. We can’t rely on our communities having space and accommodation for kids and so, well, without a family network we’re on our own.
You don’t need a gym, those are just excuses. You can do a lot right at home, and more frequently as you don’t need to go all the way to the gym every time.
Physical fitness for good health has 2 components: aerobic fitness and strength. You can improve your aerobic fitness and your upper body strength at home (rings and/or handstand pushups are enough for all but the most advanced strength athletes).
Core/lower body strength is another matter entirely. People tend to quickly progress to 1x body weight squats and deadlifts. And someone who is more advanced will probably be in the 2x-3.5x range. Without access to serious weight, lower body training is usually pretty ineffective, strength wise.
It's a bit expensive to get started, but a rack and weights will pay for itself in saved gym fees after a couple years, or a few months for 2 people somewhere expensive like SF. We managed to fit one back when my wife and I lived in 1 bedroom apartments.
> a rack and weights will pay for itself in saved gym fees after a couple years
That's been my solution.
If you take into account resale value, it'll actually pay itself off much faster - especially if you're willing to wait for good deals.
I think I was able to put together a full set of weights + another set of 45s for less than $1/lb. I'm using a cheap bar and a cheap rack, so the whole thing cost me less than $800.
I estimate that I could sell it all today for $600 for sure, and probably get back all my money if I was willing to wait 1-2 months.
The other big advantage of using a home gym is wait times; I used to go to a commercial gym, where the wait time for a rack was often more than 30 minutes at peak times. As long as you don't need machines (lat pulldown can be very nice), a rack at home can make gym time much more efficient.
I assume your parent was confused about notation. You can get 1x body weight squats (that is to say your actual body + 1x your body weight as additional load) by doing one legged squats off of a chair.
I don't understand where I'm wrong about the 2x bw though?
My thesis is that disregarding upper body gains, which can be compensated by other exercises, single leg squats will get you to 1x + 1x bw, which is 2x, with almost no gear at all.
You can also reasonably easily add about 2x15kg in dumbbells which is almost another 0,7x or so, making home training quite powerful.
> I don't understand where I'm wrong about the 2x bw though? ... single leg squats will get you to 1x + 1x bw, which is 2x
The disagreement is purely about notation.
In the strength world, people routinely ignore bodyweight when measuring squat intensity - they only list load weight. I suspect that this is, in large part, an effort to be consistent with other barbell exercises like Deadlift (which I mentioned earlier), Press, Bench Press, Row, etc. where including one's body weight wouldn't really make sense.
If you want to go really cheap, buy a kettlebell. When that becomes too easy, buy a heavier one. Unless the goal is actual powerlifting, buying a kettlebell every time you need a heavier one will carry a person a very long ways.
If a person has more money and the space, they can do the same thing with dumbbells.
It's really not complicated, but people make it so.
The big corporate gyms are dirt cheap and typically have onsite daycare for a small fee. My wife and I pay $55 a month for a family membership at LA fitness, and daycare is $5 per visit or $15 extra per month. No indoor track, though.
Planet Fitness is like $10 a month and usually 24/7. I'm sure someone will criticize planet fitness because it doesn't have x,y,z...but I don't think you can get better value for an average person.
More likely people might criticize that Planet Fitness does not exist in every country. Or it might not be close enough to everyone. Where I live the cheapest gym membership is 24€/mo and that gym is shady as hell (really bad reviews everywhere).
> The Mediterranean diet is associated with a reduction in all-cause mortality in observational studies. There is evidence that the Mediterranean diet lowers the risk of heart disease and early death. The American Heart Association and American Diabetes Association recommend the Mediterranean diet as a healthy dietary pattern that may reduce the risk of cardiovascular diseases and type 2 diabetes, respectively.
It varies slightly from person to person, but generally “lots of vegetables and minimize highly processed foods. Those are the common denominators of a healthy diet. From there, you can fill in the blanks to suit your tastes and your unique physiological needs by adding your choice of high-quality fats (nuts, seeds, avocados, olive oil, fatty fish), carbohydrates (whole grains, fruit, starchy root vegetables), and plant- or animal-based protein (legumes, soy, fish, lean sustainably raised meat, poultry, eggs, dairy).”
The only thing that is humorous and disheartening is that your outlook is shared by the majority and for this, we are fucked. The inability of large corporations to best what is available to EVERY PERSON, for FREE, is a BLESSING. All these companies do is add layers of complexity or outright push a worse product and rely on changing public opinion or how info is perceived for sales. This is capitalism's kiss of death. Their goal is not healing, their goal is removal of symptoms where you will be held in perpetual subsistence. And we should never let that be forgotten.
On a macro level if you want to improve your health : Less processed foods, less synthetic materials, less pharmaceuticals, less time sitting and indoors. Less alcohol, less weed, Less involvement from these "professionals" all across the board. Less, less, less. Wow, isn't that weird?
For those who will comment for arguments sake, I would rather you provide examples of the sitting President promoting overall good health practices (read: FREE) rather than his usual gaslighting the public into taking an untested pharmaceutical product.
People who obsess over how health care is delivered - Public, Private or whatever - should really take this to heart. The things that really make a difference to populations (as opposed to individuals) - don't over eat, don't smoke, drink moderately, get some exercise, get vaccinated - are pretty much all (except for the last one) outside the purview of doctors, nurses and hospitals. A Dr. will always tell you about those items but they have no chance of getting you to do any of that.
The people in this thread saying we should have walkable communities are being unrealistic but I'll concede that that what they're saying is better then any idea I have.
Not to be pedantic, but the number appears to be (up to) 88%, and the study involved women only.
Incredible results but I think the specifics are worth using when they’re available.
Also, there is no cause and effect here, though vascular origin dementia as noted seems almost certainly to be reduced by better cardiovascular fitness, as are many other vascular issues. Having said that, vascular and arterial lining damage due to diet appears not to be resolved by exercise, and could very easily be a culprit here as well. Fitness is a great tool for general well-being, but it doesn’t appear to be the singular cause of increased wellness here.
If exercise reduced risk of dementia by 99% would you still feel compelled to point out that it "doesn't appear to be the singular cause of increased wellness"?
Where's your threshold?
We literally have the solution. What you're saying, while it is technically true, seems to be more of an excuse or justification not to exercise. Perhaps I'm reading too much into your comment.
I think you are reading into it too much, but I think you also might be missing that fit people may tend to make a LOT of different decisions in life than less fit people.
This is something I’ve been digging deep into and discovering a lot of seemingly safe assumptions turn out not to be.
I do expect exercise is a major factor here (perhaps the largest), but I’m acutely aware lately that these things, especially where nutrition could be a significant factor, are rarely ever cut and dry. It’s incredibly complex.
I don’t mean to say people shouldn’t exercise. I should have emphasized that, without a doubt. We know beyond any shadow of doubt that it improves quality of life dramatically for virtually everyone.
Correlation is not causation. Even if exercise were associated with a 99% risk reduction, it could remain the case that people who are prone to Alzheimer's are less motivated to exercise early in life rather than the exercise preventing Alzheimer's later in life. There are plenty of other good reasons to exercise, we don't have to stretch this one beyond what the data says.
> High fitness in middle age reduces the chance of dementia by ninety percent
Not to be a sourpuss but I believe that a reasonable theory on this is that physical activity, especially activity that uses brain power, causes neuronal development which reroutes function around damage, without necessarily preventing or mitigating damage itself.
Physical surely helps but the theory of cognitive reserve suggests heavy brain use may build up a reserve of extra connections which insulate one somewhat from brain loss. I can't quote selectively as it's a big chunk of text, but here <https://en.wikipedia.org/wiki/Cognitive_reserve>
Rerouting is mitigating. If the end result is lack of dementia, that's what's important. The fact that some percentage of the neurons are damaged is not a problem. The elasticity of the brain is an evolved trait, rerouting is what the brain does to keep working.
As someone who has a close relative diagnosed with this disease, I'm always on the lookout for new information. So this is interesting.
One area I'm particularly interested in is the correlation to diabetes. It's a factor that I found being mentioned here and there in some references. In the immediate case that interests me, there's a 20+ year history of type 2 diabetes and a recent scan showed severe bilateral hypocampal atrophy. When googling for a link between the two I found this:
"Lower insulin secretion was significantly associated with HPGA (hippocampal and parahippocampal gyrus atrophy) in patients with type 2 diabetes mellitus. The results of this study support the hypothesis that insulin‐signaling abnormalities are involved in the pathophysiology of Alzheimer’s disease."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504906/
Yet, the mechanism of this, if indeed there's causality (not just correlation) does not seem to be known.
My speculation, as with others, is that Alzheimer's disease (as well as many other slow progressing diseases) is just a metabolic disease, inline with the "type 3 diabetes" comments.
Look into supporting mitochondria health [0] and the glymphatic system [1]: good diet (with fasting), light to moderate exercise, sleep and wake at the same time each day for circadian rhythm training, reduce unnecessary stress.
Once the basics have been implemented, some supplements could help to further support cell function if needed: Longevity supplements that Dr David Sinclair takes [2], boosting cellular glutathione stores, with NACET, glycine, selenium [3]
Certain medications such as metformin and SGLT2 inhibitors can be fairly effective in treating type-2 diabetes, but they don't really correct the underlying pathology. Lifestyle changes including increased exercise and greatly reducing carbohydrate consumption will do more over the long run and should be the first line therapy for patients with metabolic syndrome or pre-diabetes. Of course that won't be sufficient for some patients, and others are unwilling to make the necessary lifestyle changes.
Research has shown that many type-2 diabetes patients can put their disease into remission, or at least reduce the need for exogenous insulin, through nutritional ketosis.
I believe there are quite a few scientists that agree with you. Some are trying to rename Alzheimer's to Type-3 diabetes. There are some articles sprinkled throughout nih.gov PubMed on this topic.
I consume a lot of sugar. I’m not diabetic or pre diabetic. I would suspect underlying inflammation leads to some nasty effects. The same for heart disease.
I think I like the buzz. I go hard on hot sauce too. The endorphin rush from hot sauce is amazing. I bring a fresh bottle with me every time I go to a new restaurant. Sometimes when I leave it’s empty.
It doesn't directly contradict the paper you linked, but figured it's worth mentioning - the hypothesis about a diabetes-Alzheimer's link might have originally stemmed from fraudulent work. From the "related story" at the bottom of the linked Science article about fraud https://www.science.org/content/article/potential-fabricatio... (related story is titled "Research backing experimental Alzheimer’s drug was first target of suspicion", also available in their reader here:
https://www.science.org/doi/full/10.1126/science.ade0181?ado...)
> The most influential Cassava-related paper appeared in The Journal of Clinical Investigation in 2012. The authors—including Wang; Arnold; David Bennett, who leads a brain-tissue bank at Rush University; and his Rush colleague, neuroscientist Zoe Arvanitakis—linked insulin resistance to Alzheimer’s and the formation of amyloid plaques. Cassava scientists say Simufilam lessens insulin resistance. They relied on a method in which dead brain tissue, frozen for a decade and then partially thawed and chopped, purportedly generates chemical signals.
> Schrag and others say it contradicts basic neurobiology. Schrag adds that he could find no evidence that other investigators have replicated that result. (None of the authors agreed to be interviewed for this article.)
> That paper supported the science behind Simufilam, Schrag says, “and spawned an entire field of research in Alzheimer’s, ‘diabetes of the brain.’” It has been cited more than 1500 times. Schrag sent the journal’s editor his analysis of more than 15 suspect images in two groups. The editor says the journal analyzed high-resolution versions of the images in the first group. It could not corroborate his findings and therefore did not investigate further.
From the article: "A report in the July 2020 issue of The Lancet listed the variety of known risk factors for dementia, ranging from air pollution to repetitive head trauma to systemic infections."
The article doesn't mention diabetes or sugar.
Actually, that 2020 report[0] does mention diabetes:
>Overall, a growing body of evidence supports the nine potentially modifiable risk factors for dementia modelled by the 2017 Lancet Commission on dementia prevention, intervention, and care: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact.
There's also a lot of research out there that links diabetes to inflammation. Inflammation can be due to diet (chemical derangement) or infection or both. Inflammation is implicated in a lot of brain issues as well.
I'm aware that the parent article doesn't refer to diabetes. I never said it did. As a general comment regarding this disease I shared what my current state of mind on this was. Is there a link between diabetes and the mechanism explored in the parent, maybe? I don't know. But maybe, just maybe, if enough paths are explored we'll eventually find the right one. Diabetes seems to be an interesting one for me ... but I'm by no means an expert. Just an interested observer that is doing a genuine effort to understand.
I'm fine with most researchers pursuing a particular direction, but I get concerned when incentives align that provide a significant pressure for them to research what they wouldn't naturally want to research. It seems like there should be a distribution of research directions, not everyone in lockstep. It's hard to gauge from the outside to what degree that is happening in our research institutions today.
In theory, that's where a lot of individual NIH grants are supposed to do - K level and R level grants. However, NIH people tend to have gotten risk adverse so they look to certain parameter to "vet" whoever gets the money amongst all sorts of applications. The idea is one thing, but also - whose lab you're being mentored in, prior funding success, etc etc play an equal if not more important role.
I think the problem then is...if you have some promising directions from preliminary work, to test an idea in clinical trials, it is not cheap. You have to hire a large army of clinicians, nurses, research people, etc etc to manage all the patients/subjects x 10,000 or 50,000. So there has to be at least some politicking to steer where all the research funds go to. And people who are better at "finessing" scientific review boards tend to bubble to the top
Nobody gets a K award on their own merits. Unless your mentoring committee is well funded and walking lockstep with conventional wisdom, your application is dead in the water.
That's the sad part. Albeit one of my colleagues I know (immensely talented in his own right) is also extremely good is sniffing out who's on the NIH study section reviewing his grants, and networking with them after hours...
Study section rosters are published information. Membership is set for a period of years. Interfering with members is expressly forbidden, though no doubt it happens.
Ya a more accurate headline might be "wealth inequality found to be major cause of Alzheimer's research failures" or "Alzheimer's research failures reveal defects in western medicine".
If the fundamental problem is misallocation of research dollars, then that's what should be tackled first. I'd vote to do something like a git bisect and isolate the failures first. The scale of the failures suggests that the problems go back to the beginning. So I'd start by halving the funds that go to the big players and distributing the remainder amongst smaller groups and individuals trying a wide array of different approaches.
That said, I'd predict that as theory and simulation improve, especially in areas like big data, machine learning and AI, strong correlations will be found soon (probably within 5 years, certainly 10). They'll probably discover something that the article hints at, that the problem is actually inside cells and that the amyloid protein is a symptom (not a cause). It's probably something like a subtance in food confusing the immune system or a multi-cause effect related to living a lifetime under acute stress far above and beyond what we'd encounter while living in a hunter-gatherer society, or simply that we get no exercise compared to what our bodies evolved for so maybe the cellular repair mechanisms generated by our muscles aren't there to repair the nervous system (no blame here - it's hard for older folks to get enough exercise when they're hurting).
All wild speculation on my part as a computer geek who doesn't know the first thing about medicine, I'm the first to admit!
> when incentives align that provide a significant pressure for them to research what they wouldn't naturally want to research
The thing is, the beta amyloid theory was the only explanation for Alzheimer's that would allow treatments to be developed right now.
Tons of people want treatments asap.
While it makes no sense to develop treatments based on this theory if they definitely won't work, when it looks like there's an 80% chance of the theory being wrong, 100% of drug companies' Alzheimer's drug development money is still going to go to drugs based on this theory because we have nothing else except vague hypotheses with no drug targets.
So actually part of the problem is that so many people are incentivized to keep sticking to this theory and someone needs to step in and stop it.
There's a lot of articles recently on how we're "rethinking" Alzheimer's, and what is utterly baffling to me is the way none of them seem to mention that it has recently come to light that much of the foundational research on Alzheimer's was falsified: https://www.science.org/content/article/potential-fabricatio...
And they mention the “resistance” in the scientific community to consider causes other than amyloids which is introducing human biases into the scientific process
In many scientific research projects the same dangerous theme keeps surfacing: monolithic thinking, with “no alternatives allowed”. I feel this is very detrimental to both scientific progress as well as to the broader society.
This discussion about the cause of Alzheimer's is not new, it has been going on for something like 10-15 years at least. What is triggering the publicity now is that two drugs targeting amyloid failed to produce real improvement even though they were effective at reducing amyloid. Especially the newer one produced very large and measurable reduction of amyloid, but only very small (but measurable) cognitive improvement.
In any case the whole amyloid system is involved somehow, I think that much is very likely. Just not in the way that the visible amyloid fibers are the cause, but might just be another symptom. This is not anything like heretical talk, this suspicion was pretty much mainstream when I studied biochemistry ~15 years ago. It was only a hypothesis, but it certainly wasn't suppressed.
We have only recently had any drugs that could reduce the beta amyloid. While they do reduce the amyloid, they do not see to have an equivalent impact on the actual disease. That failure IS prompting people to reconsider other root causes, again.
that's true for any sociopolitical system, and the reason why i push back on dichotomous thinking, especially "left-right" or "democrat-republican" in political discussions. this is the central exploration of Wisdom of Crowds, which i recommend to everyone even though it's considered 'old' now.
> the same dangerous theme keeps surfacing: dangerous theme keeps surfacing: monolithic thinking, with “no alternatives allowed”
That might be part of it. I think a bigger part is, "we don't know what X is so we can't measure it, but Y seems to coincide with X and we can measure Y, so let's focus on Y".
This probably happens a lot and sometimes it works out, but it also often doesn't. It failed with dietary cholesterol, and Alzheimer's is the just the latest big failure of this approach.
I think unjustified "monolithic thinking" in this instance was bad. I'd say that's because in medicine, so many maladies are multifactorial and thus one shouldn't declare victory till your model shows strong effectiveness in the field.
But "monolithic thinking" is also accepting established theory. Unlimited diversity can open the door to all sorts of crap - I don't want "diversity" in whether a doctor accepts the germ theory of (some) disease, the existence of viruses, etc.
> Faced with the choice of either chasing cures based on amyloid or pursuing a nebulous something-more-than-amyloid, the medical and pharmaceutical communities made what seemed like the rational choice.
No one should accept this as an excuse. They weren't rational, they chased the shiny.
I'm not sure "visibility bias" already has the right meaning, but if not we need a term for this pervasive problem where people just choose to not believe or otherwise ignore factors that don't leap out to them, even if they're just as if not more important in reality. More abstractly we see it with Alzheimer's hypotheses here: Hypotheses with greater uncertainty suffer the same treatment, where not having as clear an idea about what it is causes it to be entirely discounted, for years, in favor of the clearer action plan.
The brain "takes out the trash" when you sleep.* From what I have read, the accumulation of both amyloid beta and tau are linked to sleep deprivation. They may be markers of sleep deprivation and treating the sleep deprivation may be the best thing to do, though that probably won't get someone famous for some billion dollar drug discovery, so no one will likely pursue it.
(Yes, I am aware that some of the research is possibly fraud, other avenues of investigation have been suppressed, etc. I've read quite a few articles about Alzheimer's, my late father had Alzheimer's and ...etc.)
I read a few years back about a new discovery of lymphatic system connecting to the brain. Small lymphatic veins help clean out these substances, especially during the night. One doctor cured his wife from MS using vein balloons like they use in heart conditions on these veins.
I can't verify if this was real of fraudulent information.
“As you age, the fluid movement in your brain slows, sometimes to a pace that’s half of what it was when you were younger...We discovered that the proteins responsible for Alzheimer’s actually do get drained through these lymphatic vessels in the brain along with other cellular debris, so any decrease in flow is going to affect that protein build-up.”
Lymphatic Vessels Discovered in Central Nervous System (2015)
Disturbed sleep should IMO also be looked at - eg UARS and sleep apnea. You can sleep 8h every night and still feel crappy waking up. Maybe disturbed sleep is even worse than lack of sleep?
I can feel better after 6h of good sleep than after 9h of disrupted sleep (eg when I know I‘ve been snoring, eg due to throat infection).
To my mind, they are both a form of sleep deprivation. I would say that sleeping poorly, no matter how long you lay there, still constitutes sleep deprivation.
And as people get older, they tend to both sleep less and also sleep less deeply.
Maybe it’s worse than that. If eg a long term lack of REM sleep lead to Alzheimer‘s (it seems to create dementia patterns at least), and people with disturbed sleep get virtually none of that, then they might be worse off than someone with just 5h of sleep.
Having had some very serious sleep issues in the past due to health issues, I would not disagree that sleep quality matters more than how many hours you sleep per se.
The link isn't "disturbed sleep" necessarily. As we age, sleep naturally degrades, and that degradation is in the slow-wave sleep which drives the clearing of amyloid plaques, and tau (along with hormonal response, memory consolidation, nervous system, and more).
The technology we're developing at https://soundmind.co is supporting an Alzheimer's prevention trial beginning in January '23 which is looking at the impact of slow-wave enhancement in the clearing of Amyloid plaques.
Not necessarily. Though Alzheimer's is an age related disease, and each 5 years increases the likelihood of developing Alzheimer's [1].
The older you get, the more likely you are to get Alzheimer's. Young people don't get Alzheimer's (with the exception of early onset, which is still in an older population).
So if we extend life long enough, will everyone get it?
Unlikely. Just like not everyone with high cholesterol develop heart disease. However the older we get, the worse sleep gets, the more build up of amyloids, the more likely a person is to develop Alzheimer's.
Part of the reason the amyloid theory is in question is because there are people with significant build up of amyloid who do not develop Alzheimer's and there are people with little amyloid build up who do generate Alzheimer's.
I'm not saying "disturbed sleep", which I believe you are defining as apnea or other respiratory issue, should not be looked at. But even if it is, that does not answer the age related decline in SWS.
Even if there is no other health issue, SWS declines with age. The decline of SWS is linked to increased amyloids, which is linked to Alzheimer's.
Yes, apnea also has an impact on SWS, with the same relationship to amyloids and Alzheimer's, but solving the apnea does not solve the age related decline.
What if the underlying mechanism causing Alzheimer's is responsible for the deterioration in sleep quality in the first place? If you put it simply like "bad sleep causes Alzheimer's" you make almost exactly the same mistake as the researchers who came up with Beta-Amyloid thesis: there are plaques, they must be responsible for destroying the cells. But as time has shown, the real causality is much more complex.
I agree that all directions should be explored. I wonder if there's already a database of Alzheimer patients that includes sleep quality measurements?
I agree that fixing sleep quality is not simple and that getting to the root causes of lack of sleep quality for a specific individual is the optimal means to pursue this. (I am certainly not interested in, say, promoting sleeping pills as an answer.)
Probably because, barring completely antibiotic resistant bacteria or some super-virus, if you live in a high-income area, you are either looking at dying due to your heart giving out, or your brain.
“Deaths due to Alzheimer’s disease and other dementias have increased, overtaking stroke to become the second leading cause in high-income countries, and being responsible for the deaths of 814 000 people in 2019.”
And given the nominally cerebral bent of this forum: kinda makes sense we’re freaking out about our brains throwing a kernel panic someday.
HN workers probably tend to be highly educated and the idea of slowly sinking into dementia is especially terrifying for them. The whole amyloid hypothesis has been debated for decades as well, so by now a lot of people are more familiar with alzheimers research vs others
I think it's because Alzheimer's essentially ends in people you know, turning into a person that you don't know. They basically turn into someone else.
Because that has a more direct emotional affect on those around them, it gives people a stronger desire to want to eradicate it.
Yes, I've noticed that Alzheimer's seems to be unusually popular on HN. I think much of it is the appealing narrative of those silly scientists and their amyloid hypothesis when the cause is obviously (pick one) sugar/inflammation/herpes/aluminum/tau/bacteria/immune/etc.
Heart Disease, Cancer, Stroke, Alzheimer's, and Diabetes would be an easy top 5. Covid was the third leading cause of death last year, and considering the effects on some, it likely deserves more work as well.
Respectfully I disagree and science seems to be supporting that point of view as well.
But, even if you call it a cultural issue, it is still a health issue. It causes billions in additional care, shortens lifespans, is a risk factor for many other diseases. Those facts alone make it a medical problem.
> As someone who has a close relative diagnosed with this disease, I'm always on the lookout for new information. So this is interesting.
AD is, sadly, rather common, as well as a really devastating disease: you can do nothing but watch as your loved ones become shells of themselves in front of your eyes. You can consider yourself lucky for not having gone through it personally.
I’m sorry for suggesting you haven’t, my condolences.
Besides the emotional side, AD is more of a single entity than all of cancer, as well as really costly in terms of hospice etc so financially the research is much more viable. The mystery of the mind as well as the state of the art are also a lot easier to get clicks with than “new crazy expensive drug marginally increases the prognosis of one specific type of cancer”, so the latter’s smaller breakthroughs don’t get as much publicity.
The article does in fact mention this event in the below paragraph:
"The hypothesis took another hit last July when a bombshell article in Science revealed that data in the influential 2006 Nature paper linking amyloid plaques to cognitive symptoms of Alzheimer’s disease may have been fabricated. The connection claimed by the paper had convinced many researchers to keep pursuing amyloid theories at the time. For many of them, the new exposé created a “big dent” in the amyloid theory, Patira said."
There's a couple clinical trials with various variations of young blood or blood plasma being given to Alzheimer's patients. Should be interesting to see how that goes.
It was a joke as Peter Theil has been jokingly called a vampire because he gets blood transfusions from young people in an effort to maintain his youth.
That being said, thanks for the links. I read them all.
I think there's a social element to it. My mother's cognition fell off a cliff with the social isolation during covid. Also, she has lifetime poor hearing
"... mild hearing loss doubled dementia risk. Moderate loss tripled risk, and people with a severe hearing impairment were five times more likely to develop dementia".
I liken the fight against alzheimers to the fight against aging. Isn’t it kinda the same battle? As things and people age they just break down, same thing happens to a car, as it gets older the metal rusts, the moving parts seize up and eventually the car itself suffers a catastrophic failure that ultimately results in its death. Same thing happens to people as well, the brain is like an computer in a way, except it does have actual things moving inside of it, the moving parts (Cells) get older and start to break down, ultimately leading to the death of the person.
Did anyone read "The end of Alzheimers" by Dr. Bredesen? In the book he claims to have the cure, but no one has really talked about his approach. Was it debunked? I'm confused.
Bredesen's protocol is essentially: exercise, sleep, keep your mind engaged, control any correlated issues [like sleep apnea, diabetes], treat correlated infective illness [like EBV] and take some supplements that could positively affect some cause of the illness. I think it's likely that a huge portion of his protocol will prove worthwhile in preventing Alzheimers based on probable causes outside of the AB hypothesis.
... with that all being said, my mother has early onset Alzheimer's disease (hardly over 60), and getting her on any mitigative attempts like elucidated by Bredesen is effectively impossible. She's still independent enough to live and do most things on her own, but injecting new habits has proven really challenging, as apathy is one of the most pervasive symptoms of the disease. She also had years of obstructive sleep apnea that she refused to treat, as she hated the CPAP machine.
Sure, Breseden is likely a bit of a scam artist, and it's very unlikely his protocol reverses the illness as he claims, but his ideas piecemeal are hardly "unproven" as elucidated by folks here. I think it's very unlikely that Alzheimer's finds a "cure" in a pill or some easy treatment--it seems like it's a disease that emerges after years of dysfunction, potentially from many causes, and you can't rebuild Rome overnight. I'd guess that the future of Alzheimer's research will be in prevention.
I've read it. It's about healthy diet, exercise, and sleep. Even if Dr. Bredesen is wrong, having a healthy diet, exercise, and sleep program is still going to be good for you.
He's never actually given ANY evidence to prove what he's suggesting. He's only shown clinical cases which are basically "these people followed my advice and got better" - Which isn't exactly scientific.
It's akin to me saying that if you eat one cheeseburger every day for your whole life, you'll not get dementia. Then when you don't get dementia in the next 10 years, say that it shows what I'm saying must have had some validity behind it.
I don't agree with this comparison. He does say why it would be difficult to prove his assertions on Alzheimer's, but he also brings up cases where people reversed their mental deterioration, which is unheard of. So while the case count is small, if he's telling the truth here, that's a fairly significant result. Even if it is just 1 person.
You're right, do you want to march on over with me to Columbia and let everyone there know that Dale Bredesen actually got it right and his delusional ideas have been overlooked by the entire scientific community?
Idea: I'd love a ChatGPT plugin that turns long articles like this into bullet points.
Not because I'm lazy and can't read long articles anymore (omg the attention span of young people!). Having worked in this field, I'd love to skim and find out whether there's any new information here I'm not aware of without going to filler paragraphs starting with "in a sunny afternoon in August".
Remember they need new ideas and then they need animal models with which they can test these new ideas. They had one, they had drug candidates that satisfied the model and yet nothing happened. We’ve just seen the various tries run down and smell the smoke of billions of dollars burning to ash.
It’s research not engineering and we can’t experiment on people. Huge unmet market need will keep companies trying.
So the take away here is that it's looking like the leading or up-and-coming theory now is that this is a recycling waste disposal problem within some cells in the brain, i.e. in the endosomal network? https://en.wikipedia.org/wiki/Endosome ??
Carbs cause Alzheimers. As you age, your insulin resistance rises, but you still eat the same amount (or more) of carbs while simultaneously exercising far less.
Eat a ketogenic diet and you don't have to worry about Alzheimers.
Citation? This kind of study will take at least three quarters of a century to reach such clear cut conclusions. I don't think people hanging on to pseudoscientific BS live long enough to worry about Alzheimers.
After decades of research focused on the amyloid cascade hypothesis, which claims that sticky plaques of amyloid-beta proteins between neurons are the main cause of Alzheimer's disease, many scientists are now turning their attention to deeper dysfunctions happening within cells. Some believe that the disease is caused by a variety of proteins that may be causing multiple cell dysfunctions, while others are focusing on the role of tau protein tangles, which also form inside neurons.
AFAIK Alzheimer’s is a single disease, whereas cancer is kind of a catch-all category for a huuuuge set of different disorders caused and treated by different things.
Alzheimer's is currently categorized as a single disease. But I suspect the result will turn out to be similar to Ulcers which were initially thought to be the result of acid diets, and predisposed conditions, but turns out there are many types, and the most common type is bacterial.
I think we'll find there are many types of Alzheimer's, some Amyloid based, others viral, or dietary, etc.
I think it's extremely likely it's caused by something either unknown or previously considered to be safe for humans. Would be nice to study groups of people and see their rates of this illness. Multi-group elimination diet, with HTMA and blood and bone marrow tested for presence of metals, oxidants, etc.
I think the main problem is that there's no money in saving old people. The current system we have is built around what can benefit the pharmaceutical industry the most, on a long-term basis. Old folks die too soon and often don't have much money to begin with, so sadly it's likely not high on the priority list.
Acetaminophen has numerous well-known risks and is probably more dangerous than most people appreciate, and is overused, over-marketed, and too-readily available. BUT, like some other too-simple hypotheses on this thread, it isn't giving you Alzheimer's directly. It may be part of a complex network of causes. Or not.
"High fitness in middle age reduces the chance of dementia by ninety percent" https://www.ergo-log.com/high-fitness-in-middle-age-reduces-...