Cognitive decline and rheumatoid arthritis, methotrexate

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Ob1knobi
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Cognitive decline and rheumatoid arthritis, methotrexate

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My dad (79) was diagnosed with MCI about 3 months ago (Changes in hippocampus and bleeding). Dont know APOE status yet. After talking to a doctor who practices the Bredesen protocol, we think his methothrexate medicine that he gets for his rheumatoid arthritis (RA) can potentially be a contributing factor for MCI. He wants to try going off the meds and see if it is possible to reduce the arthritis inflammation through diet / supplements. It might be worth a shot, but im worried because the meds fixed his neck-pain, which really was killing his sleep and overall health for a time. He started on a high dose about 10 years ago, but now the dose is much lower. If the neck pain starts again, and the meds dont work the next time, that would be really bad.

I have not read too much about this, but there is a case study about a person who got better after going off the methotrexate (1), and a study from 2020 of 2000 RA patients, showing 1.78 increase in vascular dementia risk for those on synthetic RA meds (like methotrexate) (2). But I also found 3 studies claiming methotrexate can reduce the chances of developing dementia (3,4,5). A new meta analysis of 14 studies finds that there is no decreased risk for dementia in RA patients with synthetic medicine. 2 of the studies (the meta analysis and the study ref number 2) also find that biological RA medicine can decrease the risk for dementia with 30% (6).

Im wondering if anyone here have had the same dilemma or know of other topics i should read up on in relation to rheumatoid arthritis and dementia. Or tips to what is the most important steps to reduce the RA inflammation?

1)Reversible Methotrexate-Induced Dementia: A Case Report
2)DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: A propensity score-matched case–control study
3)Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study
4)Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients
5)Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study
6)Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis
Lyre Taylor
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Re: Cognitive decline and rheumatoid arthritis, methotrexate

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Ob1knobi wrote: Fri Jul 05, 2024 4:39 am My dad (79) was diagnosed with MCI about 3 months ago (Changes in hippocampus and bleeding). Dont know APOE status yet. After talking to a doctor who practices the Bredesen protocol, we think his methothrexate medicine that he gets for his rheumatoid arthritis (RA) can potentially be a contributing factor for MCI. He wants to try going off the meds and see if it is possible to reduce the arthritis inflammation through diet / supplements. It might be worth a shot, but im worried because the meds fixed his neck-pain, which really was killing his sleep and overall health for a time. He started on a high dose about 10 years ago, but now the dose is much lower. If the neck pain starts again, and the meds dont work the next time, that would be really bad.

I have not read too much about this, but there is a case study about a person who got better after going off the methotrexate (1), and a study from 2020 of 2000 RA patients, showing 1.78 increase in vascular dementia risk for those on synthetic RA meds (like methotrexate) (2). But I also found 3 studies claiming methotrexate can reduce the chances of developing dementia (3,4,5). A new meta analysis of 14 studies finds that there is no decreased risk for dementia in RA patients with synthetic medicine. 2 of the studies (the meta analysis and the study ref number 2) also find that biological RA medicine can decrease the risk for dementia with 30% (6).

Im wondering if anyone here have had the same dilemma or know of other topics i should read up on in relation to rheumatoid arthritis and dementia. Or tips to what is the most important steps to reduce the RA inflammation?

1)Reversible Methotrexate-Induced Dementia: A Case Report

https://www.sciencedirect.com/science/a ... %80%932.61)]DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: A propensity score-matched case–control study[/url]
3)Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study
4)Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients
5)Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study
6)Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis
Hello!
I can see that you’ve conducted extensive research, and your dedication to helping your dad is commendable. He’s fortunate to have you as a pillar of support. I empathize with your dilemma. In my own experience, a family member struggled with severe arthritic pain. Surprisingly, after removing nightshades from their diet for two months (nightshades include potatoes, tomatoes, eggplants, and peppers), they became pain-free. As a support team intern, I warmly welcome you to this forum.

If you haven't already checked out apoe4.info, I'm happy to share several tools & resources to help you get the most out of your experience here. The Primer is a detailed and informative resource written by a practicing M.D. with ApoE4/4. It includes information about the biochemistry of the ApoE4 gene and offers a variety of research-based prevention strategies.

Some helpful tips to navigate the site include the How-To Guide. It includes topics such as navigating the forum, private messaging, and searching. One great tip is using the quote (") button when replying to a post. Using the button will automatically alert the member of your response.

Wiki Main Page contains a wealth of information.

If you are interested in learning more about other members check out Our Stories.

I am so glad you joined our forum.

While you may not yet know your dad’s Apoe status, rest assured that you’ve found a supportive community here. You’re not alone—we’re all navigating health challenges together, learning from one another and growing together.
Please reach out anytime.

Thank you,
Lyre
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SusanJ
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Re: Cognitive decline and rheumatoid arthritis, methotrexate

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Ob1knobi wrote:Im wondering if anyone here have had the same dilemma or know of other topics i should read up on in relation to rheumatoid arthritis and dementia. Or tips to what is the most important steps to reduce the RA inflammation?
Hi, and sorry your dad is going through RA.

A couple things come to mind.

Is your dad's rheumatologist tracking his folate levels? As you might know, methotrexate blocks folate use in the body. If folate levels are low, it can cause a lot of different health issues, including cardiovascular and cognitive. Here's a review article that found supplementation is appropriate. I would suggest methyl folate over folic acid, which your body has to convert and many of us may not do that conversion well).

Another thought would be to do an elimination diet, where you take known allergenic foods out of the diet and reintroduce them to see if your dad reacts. Here's an overview from the Cleveland Clinic.

And lastly, I was diagnosed with RA many years ago because my joint pain was widespread, but my RA labs were normal. Stopping gluten not long after I was diagnosed helped, but what made the biggest difference was going low oxalate about 4 years ago. It made sense oxalates were a problem for me because kidney stones run in my family, and even though I never had stones, my urinary oxalates levels were 3 times the high end the first time I was tested. I wrote up a wiki page on oxalates and it describes how to reduce them in safely in his diet.

The best supplement for joint inflammation for me has been curcumin. You can search the site for discussions about the different formulations. I take Integrative Therapeutics Theracurmin HP, 250 mg/day.

Wishing you good answers for your dad.
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TheresaB
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Re: Cognitive decline and rheumatoid arthritis, methotrexate

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Ob1knobi wrote: Fri Jul 05, 2024 4:39 am My dad (79) was diagnosed with MCI about 3 months ago (Changes in hippocampus and bleeding). Dont know APOE status yet. After talking to a doctor who practices the Bredesen protocol, we think his methothrexate medicine that he gets for his rheumatoid arthritis (RA) can potentially be a contributing factor for MCI.
Many ”safe” drugs damage mitochondria, so when I first read this, my gut thought was the methothrexate medicine was damaging your father’s mitochondria thus contributing to cognitive decline. But that was just a hunch. I did a quick, cursory internet search and found this paper, Mitochondrial Dysfunction in Rheumatoid Arthritis (Chen Ma et al, Biomolecules, 1 Sept 2022).
This article reviews the method of mitochondrial dysfunction leading to RA, the effects of mitochondrial dysfunction on immune cells, the etiology of mitochondrial dysfunction in RA, and the pathology of mitochondrial dysfunction in RA. We also outline some drugs that can exert therapeutic effects on RA which are associated with modulating mitochondrial activity.
And from the text of this paper:
6.1.1. Methotrexate
Methotrexate (MTX) is one of the most commonly used drugs to treat rheumatic diseases. MTX is structurally similar to folic acid, which inhibits the mitochondrial folate pathway by competitively inhibiting the folate-dependent enzyme, leading to a decrease in purine and pyrimidine synthesis and ultimately reducing cell proliferation [67]. In addition, MTX reduces oxidative stress by altering intracellular ROS levels and affecting mitochondrial membrane potential, which contributes to ROS production, thereby affecting cell function and survival [68]. Elevated ROS can propagate cellular oxidative stress, exerts inhibitory effects on monocytes and cytotoxic T cells, and induce T cell apoptosis, which contributes to the anti-inflammatory effects of the drug [69]. Lee et al. found that MTX can induce apoptosis in cultured synovial cells in a mitochondrial and caspase-dependent manner, which indirectly affects the inflammatory microenvironment [70]. However, mitochondrial dysfunction is also associated with adverse effects during MTX treatment. For example, MTX promotes platelet apoptosis through JNK-mediated mitochondrial damage and cytochrome c release, leading to liver injury. MTX nephrotoxicity is caused by mitochondrial membrane potential, decreased mitochondrial dehydrogenase activity, lipid peroxidation, and increased mitochondrial permeability [71,72,73].
My inclination (just my thoughts, I’m a layperson without RA) is you should concentrate on your father’s mitochondrial health. We have some information in our ApoE4.info Wiki Mitochondria

You might want to investigate Dr Terry Wahls who has MS and was able to address it largely with a diet that was focused on her mitochondria.
Ted Talk VideoMinding your mitochondria | Dr. Terry Wahls | TEDxIowaCity
Her Book: The Wahls Protocol: A Radical New Way to Treat All Chronic Autoimmune Conditions Using Paleo Principles (available from other sources, Amazon link used for convenience, not endorsement)
Documentary video: Defying All Odds - Dr. Terry Wahls - Health & Wellness - Award Winning FULL DOCUMENTARY

Because RA is an autoimmune disease, if you dad isn’t already on an anti-inflammatory diet, one would probably be of benefit. I know he’s controversial because he also hawks his line of supplements, but Dr Steven Gundry has made a name for himself treating folks with autoimmune disease. I was able to lower my inflammatory markers by following his advice. His "Plant Paradox" diet, is described in his book: The Plant Paradox: The Hidden Dangers in "Healthy" Foods That Cause Disease and Weight Gain (same disclaimer on using an Amazon link for convenience, not endorsement). Another book of his discusses the influence of diet on mitochondria: The Energy Paradox: What to Do When Your Get-Up-and-Go Has Got Up and Gone . Because of his familiarity with ApoE4, we have an introductory wiki on Dr Gundry: Dr Gundry's Protocol

Just my thoughts on the matter. I do wish you and your father the best and good health.
-Theresa
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Ob1knobi
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Re: Cognitive decline and rheumatoid arthritis, methotrexate

Post by Ob1knobi »

Lyre Taylor wrote: Fri Jul 05, 2024 6:48 am after removing nightshades from their diet for two months (nightshades include potatoes, tomatoes, eggplants, and peppers), they became pain-free
That is very intriguing that it worked that well for your family member. I have read a bit about this, and how other food proteins and leaky gut can drive autoimmune diseases. We should definitely try changing the diet a bit and see what works best.
SusanJ wrote: Fri Jul 05, 2024 9:23 am Is your dad's rheumatologist tracking his folate levels? As you might know, methotrexate blocks folate use in the body. If folate levels are low, it can cause a lot of different health issues, including cardiovascular and cognitive.
He do get folate supplements and he goes to the rheumatologist regularly, but he is not sure if they are actually tracking it. We just did blood testing for vitamin levels at the B. protocol practitioner, so we will probably soon find out if the levels are too low
SusanJ wrote: Fri Jul 05, 2024 9:23 am Stopping gluten not long after I was diagnosed helped, but what made the biggest difference was going low oxalate about 4 years ago.
Very interesting! ill definitely look into that.
SusanJ wrote: Fri Jul 05, 2024 9:23 am The best supplement for joint inflammation for me has been curcumin.
Yes ive heard that both curcumin and fish oil can make wonders, but we have not started yet due to the blood thinning effect. Seems like the MCI could be due to vascular damage. I thought i read somewhere that people with vascular dementia should be careful with these supplements, but i could not find anything about it now so i might have misread.
TheresaB wrote: Fri Jul 05, 2024 9:40 am My inclination (just my thoughts, I’m a layperson without RA) is you should concentrate on your father’s mitochondrial health.
Many thanks for your feedback! Ill start reading up on it! We are trying to follow the ketoflex diet, but considering the RA i guess it would be smart to test with different approaches and see what works best. Seems like the mitochondria healing approach might be a good place to start!

And thank you all so much for the warm welcome and your informed feedback. I really appreciate it! Its heart warming how you are all helping each other.
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