For the life of me, last week I could not find articles published around 2010/11 that claimed, due to some mechanism that reduces plaques in the brain, that people with rheumatoid arthritis were much less likely to develop dementia. Using Google, I tried several keyword searches along the lines of rheumatoid arthritis and “lowers risk of dementia” and “dissolves plaques dementia.” The only articles I found claimed people with rheumatoid arthritis were 40% more likely to get dementia. I would reach the end of the search results with no luck finding those studies and articles that I had recalled discussing with a co-worker. Maybe I was already suffering from memory loss!
Next I tried the decentralized search engine Presearch, which I had come across while reading about this year’s The Greater Reset. Using some combination of the same keywords, I found the NIH study I was looking for on the first page. I realized my error upon finding it— rheumatoid arthritis was found to lower the risk of Alzheimer’s disease, as opposed to dementia (of which it appears to increase the risk). This is the mechanism I had dimly remembered:
In addition, the brains of GM-CSF-treated Alzheimer's mice showed more than a 50-percent decrease in beta amyloid, a substance forming the sticky clumps of plaques that are a hallmark of Alzheimer's disease. This reduction in Alzheimer's plaques and associated restoration of memory was accompanied by more immune cells known as microglia in the brain. Microglia are like the body's natural garbage collection cells that rush to damaged or inflamed areas to get rid of toxic substances.
The researchers suggest that GM-CSF boosted during the immune system overdrive of rheumatoid arthritis helps harness the beneficial properties of inflammation in the brain. The protein may do this by recruiting more microglia from the peripheral blood into the brain to remove Alzheimer's plaques, Dr. Potter said. An apparent increase in neural cell connections in the brains of the GM-CSF-treated mice may also help explain GM-CSF's association with improving memory decline in Alzheimer's disease, the researchers said.
Adding the keyword “GM-CSF” brought up more recent pieces regarding RA and AD, such as this 2017 article. I returned to Google and added the “GM-CSF” keyword to rheumatoid arthritis and (the erroneous keyword) dementia, and immediately brought up the 2010 NIH study. I next tried Brave, using the initial erroneous keywords “rheumatoid arthritis lowers risk dementia” and on the first page brought up a 2016 study demonstrating a negative relationship between rheumatoid arthritis and Alzheimer’s disease.
Although I initially began using alternative search engines due to privacy concerns, I had long felt that Google delivered superior search results. This may no longer be the case. At the very least, it appears that other search engines should be used as backup when Google doesn’t deliver.
As a side note, the long-accepted connection between Amyloid plaques and Alzheimer’s disease has recently come under question; the 2006 study that this theory was based on may have falsified images. A new study from the University of Cincinnati, OH suggests that Alzheimer’s symptoms are caused not by insoluble amyloid plaques but by a decrease in the soluble beta-amyloid essential for cognitive function. If this study is correct, it brings into question one of the conclusions of the 2010 study regarding the AD inhibitory mechanism of GM-CSF, namely that a decrease in beta-amyloid is a positive factor in preventing Alzheimer’s disease.
“Following the science” turns out to be a long and winding road indeed.
Top Image: Noun Alzheimer Nithinan 2452316.svg/ Wikimedia Commons
There are studies about the connection between Amyloid placques & Alzheimer's that predate the 2006 study you refer to. When I lived in NY I worked for Paul Greengard who was doing research on that subject in the 1990s, and won a Nobel Prize in Medicine in 2000 for his findings.
My own area of concern is the correlation between vasomotor symptoms and dementia. But anything women-only is low priority on the research funding scale so I'm not going to see a definitive answer in my lifetime, much less safe and reliable preventive measures.
Although the Nobel prize isn't any longer what it once was, I basically agree. But it isn't just women-only research that's getting short shrift. In the dementia arena, virtually ALL of the dollars have been going into ways to reduce amyloid plaques for the last twenty years. There have been other avenues of research that might yet prove fruitful that have languished because they could not attract any dollars.
I've always been struck by something Paul Graham once said in reference to startup investments. He said (paraphrasing) whenever he started hearing "best-practices" arguments he turned off and looked elsewhere. In startups, 90% of them die. Best practices means do what everyone else is doing, which is dying. The ones that end up succeeding are the ones that do something different. Well, scientific research is similar to startups in a way. More and more people are realizing that the majority of research ideas are wrong, and that the studies can't be replicated, or come up with different results - never mind the fraudulent ones. I think that some of these seemingly intractable problems in medicine are suffering from the problem that everyone is looking in the same place for answers. Like the cop who finds the drunk crawling around on the ground looking for his keys under the streetlight. "Where did you drop them?" "Over there" the guy points into a dark alley. "Well, why are you looking over here then?" "Because it's light over here."
He also dislikes statins and personally I would refuse to take them but my mom was on them for a stroke and I didn't feel like I could make the decision for someone else, so I didn't take her off them until a doctor agreed it was time to do so.
I read a long article a couple months ago about the controversy with amyloid plaque therapies in Alzheimer's the theme of which was it was a modern example of "research capture", where a popular theory that makes big careers for key people has a hard time being objective about it's ultimate results, which in this case have been basically nothing. There were a number of key papers involving outright fraud which are still being investigated. But there were also many which just ended up looking like bad study designs through poor selection of study subjects, primarily. I can't find the paper I read about it at the moment, so I'm operating on memory here. I was left with the impression that it's looking increasingly likely that the amyloid plaques may only be symptoms and not causes, so all these therapies they've come up with to reduce them aren't actually curing anyone. And - because of the way modern medicine is working - huge dollar amount grants are at stake and the stake holders do not want to own up to what they're finding because then their money dries. up. There's a bit of discussion of it here: https://www.jax.org/news-and-insights/jax-blog/2020/june/moving-beyond-amyloid-to-treat-alzheimers-disease but this is just a pop-article. If I can think of where I found that other one I'll post it. It was pretty detailed and interesting.
There is an analogy with the cholesterol-reducing drug theories. In spite of the fact that more Americans than ever before are taking them, and are actually experiencing controlled cholesterol levels, American lifespans are decreasing. Significantly. Correlational, of course. But even the controlled studies of good design cannot show mortality benefit for people taking statins (who have never had a heart attack. They can only show it for those who have had heart attacks already).
I'm going to write another piece that is going to (briefly, since it will not be the main topic of the piece) touch on the way scientific research is being conducted.
This is a valuable look at an alternative search engine for biomedical research: thanks for spotlighting Presearch!
One sentence also jumped out from this post: "This reduction in Alzheimer's plaques and associated restoration of memory was accompanied by more immune cells known as microglia in the brain."
Some tantalizing hints on the key role of microglia – and also possibly astrocytes – in various types of dementia, and even perhaps in neurological diseases like Parkinson's:
This article describes hints "pointing toward the conclusion that both Alzheimer’s and Parkinson’s may be the results of neuroinflammation—in which the brain’s immune system has gotten out of whack. ... as more genes involved in Alzheimer’s have been identified, [some research] traces nearly all of them to the immune system. Finally, neuroscientists have paid attention to cells that had been seen as ancillary—“helper” or “nursemaid” cells. They have come to recognize these brain cells, called microglia and astrocytes, play a central role in brain function—and one intimately related to the immune system." (And yes, as referred to in the post and in some comments here, beta-amyloid plaque buildup may be an Alzheimer's symptom, not a cause.)
Here's an early but perhaps notable finding that macrophages – among which, microglia are a type of macrophage that resides in the brain – become less effective in their tissue maintenance and injury repair activities with age and can even themselves contribute to inflammation, due to losing "their ability to take up and use calcium." This discovery, if borne out, might suggest promising research directions for therapies:
Good catch! Too bad the Scientific American article only touched briefly on the role of microglia, but it sounds like that could be a new area of research.
There are studies about the connection between Amyloid placques & Alzheimer's that predate the 2006 study you refer to. When I lived in NY I worked for Paul Greengard who was doing research on that subject in the 1990s, and won a Nobel Prize in Medicine in 2000 for his findings.
My own area of concern is the correlation between vasomotor symptoms and dementia. But anything women-only is low priority on the research funding scale so I'm not going to see a definitive answer in my lifetime, much less safe and reliable preventive measures.
Although the Nobel prize isn't any longer what it once was, I basically agree. But it isn't just women-only research that's getting short shrift. In the dementia arena, virtually ALL of the dollars have been going into ways to reduce amyloid plaques for the last twenty years. There have been other avenues of research that might yet prove fruitful that have languished because they could not attract any dollars.
I've always been struck by something Paul Graham once said in reference to startup investments. He said (paraphrasing) whenever he started hearing "best-practices" arguments he turned off and looked elsewhere. In startups, 90% of them die. Best practices means do what everyone else is doing, which is dying. The ones that end up succeeding are the ones that do something different. Well, scientific research is similar to startups in a way. More and more people are realizing that the majority of research ideas are wrong, and that the studies can't be replicated, or come up with different results - never mind the fraudulent ones. I think that some of these seemingly intractable problems in medicine are suffering from the problem that everyone is looking in the same place for answers. Like the cop who finds the drunk crawling around on the ground looking for his keys under the streetlight. "Where did you drop them?" "Over there" the guy points into a dark alley. "Well, why are you looking over here then?" "Because it's light over here."
Good points.
You might find this interesting: https://sensiblemed.substack.com/p/does-anyone-still-care-about-data?utm_source=%2Fsearch%2Falzeimers%2520research&utm_medium=reader2
Thanks for the historical correction. A Midwestern Doctor has other theories on the causes of Alzheimer's: https://www.midwesterndoctor.com/p/why-are-the-big-banks-targeting-covid
He also dislikes statins and personally I would refuse to take them but my mom was on them for a stroke and I didn't feel like I could make the decision for someone else, so I didn't take her off them until a doctor agreed it was time to do so.
I read a long article a couple months ago about the controversy with amyloid plaque therapies in Alzheimer's the theme of which was it was a modern example of "research capture", where a popular theory that makes big careers for key people has a hard time being objective about it's ultimate results, which in this case have been basically nothing. There were a number of key papers involving outright fraud which are still being investigated. But there were also many which just ended up looking like bad study designs through poor selection of study subjects, primarily. I can't find the paper I read about it at the moment, so I'm operating on memory here. I was left with the impression that it's looking increasingly likely that the amyloid plaques may only be symptoms and not causes, so all these therapies they've come up with to reduce them aren't actually curing anyone. And - because of the way modern medicine is working - huge dollar amount grants are at stake and the stake holders do not want to own up to what they're finding because then their money dries. up. There's a bit of discussion of it here: https://www.jax.org/news-and-insights/jax-blog/2020/june/moving-beyond-amyloid-to-treat-alzheimers-disease but this is just a pop-article. If I can think of where I found that other one I'll post it. It was pretty detailed and interesting.
There is an analogy with the cholesterol-reducing drug theories. In spite of the fact that more Americans than ever before are taking them, and are actually experiencing controlled cholesterol levels, American lifespans are decreasing. Significantly. Correlational, of course. But even the controlled studies of good design cannot show mortality benefit for people taking statins (who have never had a heart attack. They can only show it for those who have had heart attacks already).
I'm going to write another piece that is going to (briefly, since it will not be the main topic of the piece) touch on the way scientific research is being conducted.
This is a valuable look at an alternative search engine for biomedical research: thanks for spotlighting Presearch!
One sentence also jumped out from this post: "This reduction in Alzheimer's plaques and associated restoration of memory was accompanied by more immune cells known as microglia in the brain."
Some tantalizing hints on the key role of microglia – and also possibly astrocytes – in various types of dementia, and even perhaps in neurological diseases like Parkinson's:
https://www.scientificamerican.com/article/for-alzheimers-sufferers-brain-inflammation-ignites-a-neuron-killing-forest-fire/
This article describes hints "pointing toward the conclusion that both Alzheimer’s and Parkinson’s may be the results of neuroinflammation—in which the brain’s immune system has gotten out of whack. ... as more genes involved in Alzheimer’s have been identified, [some research] traces nearly all of them to the immune system. Finally, neuroscientists have paid attention to cells that had been seen as ancillary—“helper” or “nursemaid” cells. They have come to recognize these brain cells, called microglia and astrocytes, play a central role in brain function—and one intimately related to the immune system." (And yes, as referred to in the post and in some comments here, beta-amyloid plaque buildup may be an Alzheimer's symptom, not a cause.)
Here's an early but perhaps notable finding that macrophages – among which, microglia are a type of macrophage that resides in the brain – become less effective in their tissue maintenance and injury repair activities with age and can even themselves contribute to inflammation, due to losing "their ability to take up and use calcium." This discovery, if borne out, might suggest promising research directions for therapies:
https://medicalxpress.com/news/2023-07-inflammation-discovery-aging-age-related-diseases.html
Good catch! Too bad the Scientific American article only touched briefly on the role of microglia, but it sounds like that could be a new area of research.