For decades, scientists have concentrated on what now looks to be a blind alley.
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What’s the deal with Alzheimer’s disease and amyloid?
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Spoken as someone who actually started on the path of this as a research topic years ago, before life got in the way, luckily I suppose: I hope the frauds [...skips stuff that would get me in trouble...] and their engines blow out at 100 001 miles on their new cars, and their cell phones at 366 days for the rest of their lives.
More constructively, validating others' results and testing their conclusions is real science. Not as glamorous but obviously undervalued, as demonstrated here.
More constructively, validating others' results and testing their conclusions is real science. Not as glamorous but obviously undervalued, as demonstrated here.
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I was coming to the comments to compliment you on an excellent article outside your automotive beat.
My only nit would be to say that we have developed a clinically-demonstrated vaccine that actually has a measurable improvement in Alzheimer's prevention and symptom progression. Beth Mole wrote about it in February. The entire Alzheimer's research community should have massive egg on their face as far as the shingles vaccines are concerned. The accidental protection afforded by them has far more clinical data supporting its use to mitigate effects of Alzheimer's than anything targeting amyloids. That particular footnote should have probably made it into the article somewhere.
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My guess, and it is just a guess as I am just a lowly retired pharmacist, is that the amyloid is a result of the disease causing pathology, not the cause.
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The amyloid plaque hypothesis is arguably the canonically cautionary tale that correlation is not necessarily causation.
There have been those (like Derek Lowe on his 'In the Pipeline' blog) who've been drawing attention to all the drug failures and what that might imply for a long time.
Don't even mention how much money has been spent on this to date.
There have been those (like Derek Lowe on his 'In the Pipeline' blog) who've been drawing attention to all the drug failures and what that might imply for a long time.
Don't even mention how much money has been spent on this to date.
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Feel free to do that again! Very nicely written and informative piece.
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I find it interesting and probably more than co-incidental that the vast majority of cases of scientific fraud and misconduct occur in clinical/pharmaceutical research fields. When there's so much money to be made, there's an almost irresistible incentive to cut corners if not commit outright fraud.
It's far less common to find incidents of fraud among researchers working on fundamental, curiosity-driven science. Maybe if we directed more resources to publicly funded academic research this would be less of a problem?
It's far less common to find incidents of fraud among researchers working on fundamental, curiosity-driven science. Maybe if we directed more resources to publicly funded academic research this would be less of a problem?
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I'm very interested in the studies recently done on lithium orotate cited in the article above. This looked extremely promising, and was based on extensive, broad research performed over many years.
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Dr. Gitlin - your thoughts on white matter disease vs Alzheimers would be cool to read. Dad had Alzheimers and I have advanced white matter disease. Balance, route finding and task switching already taking a hit. It's an odd feeling when something else doesn't work right, my brain notices and is like yeah, not today.
Edit to add: and migraines. My neuro doc mentioned possible link in my case to migraines. FWIW, I took 5 doses of a CGRP antagonist and was migraine free for quite a few years.
Edit to add: and migraines. My neuro doc mentioned possible link in my case to migraines. FWIW, I took 5 doses of a CGRP antagonist and was migraine free for quite a few years.
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This is some beautiful low-key vindictiveness. It's a wish the monkey paw would grant without even curling a finger.
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Great to see a mainstream article recognise the staggering scale of groupthink over the amyloid plaque hypothesis.
The utter failure of tackling amyloid plaques in Alzheimer's disease seems to be having real blowback in terms of little-to-no willingness from pharma to invest in related research, which is a shame as amyloids don’t just form disordered plaques/tangles, they also form more ordered structures that can interact with other factors cited in the article as part of an ensemble of factors driving neurodegenerative conditions, and whose existence has been known for for decades - all ignored in favour of the flawed plaque hypothesis.
The utter failure of tackling amyloid plaques in Alzheimer's disease seems to be having real blowback in terms of little-to-no willingness from pharma to invest in related research, which is a shame as amyloids don’t just form disordered plaques/tangles, they also form more ordered structures that can interact with other factors cited in the article as part of an ensemble of factors driving neurodegenerative conditions, and whose existence has been known for for decades - all ignored in favour of the flawed plaque hypothesis.
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I honestly thought there had been a mixup in the author section. I have only ever read his automotive related articles.
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From what I've seen of the research over vitamin b1 (thiamine) and Alzheimer's, dietary changes offer only minimal benefit if any. There is a therapeutic trial going on where they use a thiamine precursor to boost brain levels of B1 very substantially. Pre-trial research has shown a reduction of cognitive impaiment progression in early-stage Alzheimer's patients, but data is obviously still pending from the full trial. So assuming that research bears fruit (and there have certainly been decades of hopes for treatments that didn't pan out) then it is an interesting and potential useful treatment.
Eating better is a good idea generally, but the idea that that improving b1 through diet will significantly prevent or slow Alzheimer's is simply bullshit.
Eating better is a good idea generally, but the idea that that improving b1 through diet will significantly prevent or slow Alzheimer's is simply bullshit.
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Does she have dementia or does she have cognitive impairment from a condition like beriberi which is usually quickly and effectively reversed with lots of vitamin B1?
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Yes, deficiency of Vitamin B1 can cause cognitive impairment, just as deficiencies of Vitamin B6 and Vitamin B12 can. But that's not Alzheimer's dementia even if it can coexist with Alzheimer's dementia.
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Great article. I was working on my PhD in the early 2010s in Chemistry and I could see how distorting the beta-amyloid hypothesis was. Obviously I had no way to know it was built on a pyramid of lies, but seemingly everyone who needed an excuse to pursue something would find a way to say it helped learn more about beta-amyloids. Ultra-fast spectroscopy, quantum and molecular dynamics simulations, biochemical pathway exploration....so much money wasted studying a seemingly pointless target.
I have enough trust in the scientific enterprise to know that important things were still learned from those studies. And perhaps the improvement in techniques, the students trained and the knowledge generated will still have some sort of societal return in the future that's just hard to track.
But in an era when funding for good science was hard to come by and when people were just starting to realize that the pathway to a career as an academic was dead, I can't help but think about all the people with great ideas who weren't susceptible to the groupthink. Which one of those ideas was actually brilliant? With the decline of US science funding, we may never know...until the Chinese do it.
I have enough trust in the scientific enterprise to know that important things were still learned from those studies. And perhaps the improvement in techniques, the students trained and the knowledge generated will still have some sort of societal return in the future that's just hard to track.
But in an era when funding for good science was hard to come by and when people were just starting to realize that the pathway to a career as an academic was dead, I can't help but think about all the people with great ideas who weren't susceptible to the groupthink. Which one of those ideas was actually brilliant? With the decline of US science funding, we may never know...until the Chinese do it.
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Nora Lenderbee
Ars Tribunus Militum
Keep an eye out for an article by Beth Mole about automobiles. If that happens, we'll know something weird is afoot.
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I can't even imagine what kind of lunch-ruining car pictures Beth would have to hide behind a link
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You may want to include this one:
https://pmc.ncbi.nlm.nih.gov/articles/PMC6459027/
of course there has been and continues to be a market for supplements over the life of individuals.
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No doubt it will have something about ghastly engine oil sludge.
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At various times I have been adjacent to Alzheimer's research, while avoiding being actively involved. A very difficult field, but it was evident from the beginning that amyloid plaques suffered from the cart and horse conundrum, and maybe clearing amyloid would be beneficial, but equally well maybe not. Was it the cause (seemed improbable) or an effect, and if it was an effect was it in itself causing further damage, which was quite plausible. So the experiments were worth doing, but should not have become the whole ball of wax. One of the things which puzzled me was the absolute lack of interest in our AD colleagues over the role of the intramolecular large fragment of the APP. Does it behave differently after the amyloid cleavage has occurred? Does it tie into various cellular signaling pathways, like most transmembrane proteins with a prominent intracellular domain? There are cell surface receptors which are activated by proteolysis. Is APP one of them? Does the APP cleavage, or something else tie in with the obviously damaging, like punch holes through cell membranes, phosphorylation of Tau, and formation of paired helical filaments? There just seemed to be a lack of curiosity about other explanations.
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That line right there undermines your entire post because it displays a lack of understanding of the source of the papers. The papers are not from the NIH. Your links are to the National Library of Medicine, which is a database of papers from many journals, including some of questionable value. Your first link is from Alzheimer's Research & Therapy, while the second is from the Annals of the New York Academy of Sciences.
In addition, just reading the abstracts, both papers note correlation and not causation. Both are interesting, but if B1 were the solution, it would have been pinned down decades ago.
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I think this is a quite popular position. Not mentioned in the article, but as far as anybody knows beta-amyloid is part of the brain's immune response! So if the brain was (or thought it was) fighting off a viral infection you'd expect to see it overproduced. I learned about that... a decade ago? Something like that. To me the weirdest part of the whole 'beta amyloid' controversy is how slowly it's moved. People have doubted it for decades but the research pipeline just ground on.
I quite strongly disagree here. It may be correct(ish) to say that the majority of discovered or reported or fraud anybody seems to care about is in clinical fields, but very very few other fields have billions of dollars invested on the back of that fraudulent research, and investors want to know why their billions of dollars turned into smoke and drifted away.
We've moved from a replication crisis into a shit-tsunami in the scientific literature. I believe in science as an endeavor and it still slowly triangulates towards as close as we can come to truth... but damn it's rough at the moment.
I don't think public funding actually helps on this. If you're working a niche field nobody else will ever care about, and one more paper this year means you're secure in your position... why not exaggerate the importance of this obscure protein? Frankly as person who chose industry over science, I feel like industry has stronger incentive to be honest. They don't share mind you, but they're usually honest internally because like I said about pharma, they care about wasting money on ideas that don't pan out.
I guess that brings us back around to pharma being evil, because there is no way the pharma researchers looked at their data and went, "Yup, that's a theory proved out right there." Somewhere internally there's a pile of burnt documents that say, "This is crap and we should bin it."
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This is wise. Exercising muscles has been associated with protection against Alzheimer's (https://www.alzheimersresearchuk.or...long-exercise-could-protect-against-dementia/)
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I think this is one of the major problems with how we do scientific research. I've been doing research for 30 years (eek) and see, time and time again, that we cleave to ideas that have entered scientific cannon, yet have done so based upon pretty scant data that was never rigorously replicated. Because rigorous replication is hardly sexy science nor particularly easy to get funding for. I confess I have been guilty of this sin, time and time again. But the high points of my career have been when I've, by luck or persistence, pulled the curtain back to find not the paradigmatic unquestionable wizard, but just a little man pulling some levers
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I am not surprised by this article. In fact during my grad school in late 90s, I was taught that while beta amyloid was more likely to be a consequence of the disease than the cause and that targeting may or may not have an impact. The idea of just targeting it was considered stupid by my teacher back then
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Nora Lenderbee
Ars Tribunus Militum
There are studies showing that folks who take the Shingles vaccines have a reduced chance of developing dementia.
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It's looking like this may be true for other vaccines as well, and that maybe there's a link with reduced inflammation in general leading to lower dementia rates.
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My dissertation involved some crystallographic work in this field (not amyloid fibrils). I want to add from my experience (from my brief time in the field) there seems to be a real lack of understanding as to what APP really does, and even less of an understanding as to what the closely related family members APLP1 and APLP2 do. This is remarkable considering how this protein has been studied heavily since the 90s. From a biological standpoint I don't find the previous associations with copper transport at all convincing and definitely not held up by modern studies.
It's obvious that the APP family members have extremely important roles in neurodevelopment (many, good in vitro and in vivo studies here), but I'm confused from my current interactions with people still involved in the field how little effort is made to understand what these proteins actually do.
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As someone who has this terrible disease run in their family and whose mom was just moved up from mild to moderate dementia, I really hope we find something. I just feel that this being such a complex disease, we won’t find anything to markedly slow it down. However I did on here not too long ago that people who took the Shingrix vaccine did have lower chances of developing this. The studies were early, but still relatively promising.
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I found this quoted bit above quite interesting, could it be that Alzheimer's is associated with people who carry part of the genetic defect needed to cause down syndrome in their DNA, but not all of it?
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