Dementia risk linked to blood-protein imbalance in middle age
nature.com
nature.com
I just got funded as PI to study blood proteomics and long term cognitive outcomes after large vessel stroke, with a focus on early identification of post-stroke dementia. It's a very cool area to be in.
What are your thoughts and the general consensus within your field for how individuals might prevent dementia?
Are there untested, but plausible hypotheses for the causal mechanisms -- perhaps chronic inflammation, liver or metabolic disease, bad gut microbiota, a multitude of factors? Or does more data need to be gathered?
Good overviews here https://comis.med.uvm.edu/vic/coursefiles/MD540/MD540-Protei...
and https://www.promega.com/resources/guides/protein-analysis/pr...
I always thought proteins were too big for some of these techniques but apparently not.
Thank you for your work
Aside from good sleep are there any evidence based practices for mitigating these risks?
Also: Congrats on the funding!
The article doesn't provide specific steps on how to influence the levels of these proteins. The purpose of this research seems to be more about identifying potential biomarkers for early detection and risk assessment of dementia rather than outlining therapeutic interventions.
Edit:
GDF15, or Growth Differentiation Factor 15, is a protein that is naturally produced by our bodies. It's a stress-responsive cytokine, meaning that it's part of the body's response to conditions of stress or damage. It has roles in various physiological and pathological processes, including inflammation, metabolism, and apoptosis (a form of cell death).
In terms of influencing GDF15 levels, most research so far has been in the context of pharmaceutical interventions, particularly in relation to conditions such as cancer and cardiovascular disease.
But how often does the medication development process check the result we care about: "does this medication then go on to reduce the chance of dementia?"
Good, because poor sleep habits earlier in life have been strongly correlated with development of dementia later in life.
Our time is short.
So avoiding them would be a good place to start.
https://www.uniprot.org/uniprotkb/Q99988/entry
https://www.sciencedirect.com/science/article/abs/pii/S01637....
Is also causes insulin release.
But NSAIDs have been linked to dementia in the past, so…
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/
it would be pretty crazy if drug companies were causing all of the dementia and Alzheimer’s, wouldn’t it?
This makes sense from 10k feet. If you perennially treat conditions in the body to reduce symptoms, but the conditions persist, aren't you just masking the inflammation/trauma that accumulates? Perhaps this is the best we can do for the human condition, with current technology.
Dementia terrifies me. My dad died last year with Lewy Body Dementia. After witnessing this, I totally understand why Robin Williams decided to end his life.
Had I not found the cause, I would still be popping Advil almost daily. Of course, my issue and solution is almost certainly vastly different from yours or any other person, but the key was finally discovering the underlying cause. That was the tough part.
All that said, the damage has been done, hopefully the dementia doesn't set in anytime soon. My mother just died this year with dementia, it was NOT an easy ride.
I'm very sorry to hear about your mom.
Ibuprofen, Tylenol, and indomethacin have never helped me for cluster headaches, often leading instead to rebound headaches of a different kind. The three things that help me are oxygen, sumatriptan injection, and verapamil.
The number one thing that helps stop my episode is oxygen: 15Lpm or so of pure oxygen through a non-rebreather mask. A concentrator probably won't do the trick. If you have daily episodes, you can go through an MM tank in a month.
My second choice is an Imitrex (sumatriptan) injection with a STATdose pen. Pills are worthless. The 4mg dose is just as effective as 6mg, so I can take three doses if I'm having a bad day. (The daily limit is 12mg.) They sometimes make me feel funny, and the headache occasionally comes back in an hour or two.
Verapamil helps reduce the frequency and intensity of my headaches. It has a tendency to lower my resting heart rate: I was below 40bpm one morning, and I'm not a runner.
Good luck. Clusters aren't fun.
https://web.archive.org/web/20210119212133/https://vitamindw...
If you decide to try Verapamil make sure you get the extended release pills. I don’t have the link handy but you can find research journal articles that help nail down dosage. As for the oxygen, you may have to get your own regulator and mask to get what you need. 15lpm and a rebreather mask works amazingly for me. If your doctor is difficult about it just get them to write a script for oxygen, find a local supplier and pay out of pocket. It was only $80 to rent the tanks I needed to get me through my last cluster season.
A couple of home remedies I’ve tested and found effective were cardio and putting my feet in some super hot water. Both sound silly but seem to work in my experience. So if you don’t have the other stuff yet, or aren’t able to get to it in time, give either a try. I do burpees as soon as I feel one coming one (and after I’ve chugged a 5 hour energy).
The last and most effective solution is LSD or Magic mushrooms. If you micro dose then periodically you can go a lot longer between cluster headaches. A tiny bit of mushroom also seems to work as an abortive for me when I feel one coming on.
I’m still experimenting and learning. But hopefully this info may give you some things to research or try (assuming you haven’t already, but I’d much rather share this information repetitively then not share something that could help you).
Feel free to reach out if you ever want to chat. Always down to provide research I’ve found out just lend an ear, I know how debilitating and isolating they can be.
I take quite a lot of vitamin D (6000 IUs daily), cetirizine (zyrtec), and nicotinamide riboside (300 mg), and a cheap multivitamin. I'm a little wary about adding stuff to that but I'm definitely going to look into all the things you've mentioned.
Psychedelics are super interesting to me but I really wouldn't know where to start. I'm 53 ferchrisakes. Last time I was around people buying mushrooms was 35 years ago at a skate park.
> just lend an ear
Say... that reminds me. Tinnitus isn't something you are dealing with as well, is it?
One last thing worth looking into is the link between vasodilation and cluster headaches. There seems to be a direct link. I think some of the theories are that the dilation of the major blood vessels in your brain pushes down on nerves like your occipital nerve. That seems to track with the areas I experience the most pain. I’ve experimented in the past with vasoconstrictors as a way to ease the pain. Both caffeine and psychedelics are vasoconstrictors for example. And they seem to be the two most agreed upon remedies. I believe exercise is also a vasoconstrictor, which may be why intense cardio seems to help me when the headaches start to come on.
Not sure where you live, but while not legal, you can order micro dose (100-200mg) mushroom capsules online in Canada.
I disagree that it is the best we can do. I have essentially cured my self of an "incurable" disease, one which was treated with drugs that masked the symptoms while my nervous system kept collapsing. when doctors see my labs and I tell them my story they are uninterested. That has nothing to do with technology and everything to do with curiosity and compassion.
My mother was told to take a baby aspirin everyday for her heart. Then the doctor one day to her just to stop taking them. It turns out that "just stopping" casued her to have a mini stroke (TIAs) which was well known issue when stopping long term low dose aspirin. That, and the fact that psychiatrists killed my nephew with medications, has led me to truths about the medical and pharmaceutical industries that see them as an obstacle to human health.
From other research, I suspect we can influence things. Certain populations (based on lifestyle choices / environment) have lower rates of dementia than other places.
Edited to remove Tylenol and replace it with ibuprofen. For some reason I thought Tylenol wasn’t ibuprofen. Thanks!
People overdosing on it is actually the primary cause of liver-failure--sometimes associated with people trying to handle the pain of withdrawal from some other drug--and liver-failure is a terrible way to go.
These are correlated to dementia risk, but that doesn’t mean they’re directly involved causing dementia. They could be a related effect of the root cause(s) of dementia.
There are many examples in medicine where we’ve attempted to directly modify measurable markers like this without fixing the underlying disease.
They could be useful clues for discovering the root cause, though!
The proteins from the Mendelian randomization also don't have to be (can be in a pleiotropic pathway) but there is at least reason to think that they could be causal.
Or correcting the protein imbalance could interfere with an important feedback loop that we don't yet understand, which could possibly make the situation worse. Or maybe the protein imbalances are involved in counteracting the issue that causes dementia, and that's why they're elevated.
This is a common theme in biological systems. A good example would be cortisol, which has become known as the "stress hormone". Many people assume that lowering cortisol must therefore be a good thing, but if you were to indiscriminately lower cortisol during periods of stress you'd end up in a far worse condition than you were before. Cortisol is part of your body's reaction to stress and part of the system that responds to it, so artificially lowering it can interfere with your stress response process.
Indeed it is. Tylenol, for instance, is marketed as a fever reducer.
"The Effects of Different Diets on Guinea Pig Health, Hair Morphology and Blood Protein Concentration"
~ "Guinea pigs (Cavia porcellus) have biological similarities to humans, which make them a suitable animal model in multiple fields of research. "
>People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease.
>Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier.
>Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren.
Pair that with this part of OP:
>This regulation is important in preventing proteins from going rogue and clumping together, which is what happens to the amyloid and tau proteins in the brains of people with Alzheimer’s disease, the most common cause of dementia.
I'm just a layman, but it sounds like BBB health is a major factor for regulating this in the brain. In some individuals, including those with identified genetic biomarkers for increased Alzheimer's risk, the BBB ages faster, leading to decreased regulation of protein/peptides. So learning more about how to improve BBB health could eventually help people maintain a healthy brain longer.
Avoiding excessive alcohol seems to be an important factor for BBB health, according to this 2021 study performed on mice: https://pubmed.ncbi.nlm.nih.gov/33516661/ ; also this research published in 2022: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204474/
OP refers to "amyloid and tau proteins" while the 2021 article I referenced refers to "amyloid beta peptide" - at this point, I'm really not sure how precisely these terms are being used. Are they interchangeable in this context, or is there an important nuance that I'm missing?
So, as other posters suggested, those proteins can be the effect markers but not the root cause indicators.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/
I’m not saying that it isthe root cause at all either, I’m saying they’re a marker as well. I’m saying there a marker as well, possibly from NSAIDS.
If someone is given aspirin under those conditions, they may experience a worsening because aspirin provokes the release of cytochrome C from mitochondria, thus inducing apoptosis (cell death). This is a well-known effect [0] which may lead to encephalopathy under harsh conditions [1] (in reality regardless of age). At the same time, if someone is being administered aspirin in parallel to a correction of the declining mitochondrial function, the effect is the opposite: marginal cells may still die due to apoptosis, but newer cells will be created to take their functions thanks to the increased neurogenesis as the direct result of a restored anabolism. At the same time, anti-inflammatory effects of NSAID help to suppress a low-grade inflammation in vessels' endothelium. The result is: improved blood flow which in turn helps to restore mitochondrial function even further; the loss of marginal tissues similar to autophagy, improved neurogenesis; and sometimes - dementia reversal.
BTW, this is why the results of using NSAIDs are different for younger and older cohorts - younger people have fewer chances of acquiring a compromised mitochondrial function. However, mito problems may occur even in young age due to genetics, environmental conditions, toxins, post-bacterial or post-viral effects caused by oxidative stress. So, this should be kept in mind as NSAIDs may indeed worsen the condition causing damages similar to Reye's syndrome unless they are administered together with a mito protocol.
Another important point is that different NSAIDs have different effects. Aspirin is a relatively well-regarded medication, while others may be associated with an increased risk of a heart attack or stroke - which may significantly increase the chances of acquiring a dementia, but in a different way.
[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508093/
[1] https://pubmed.ncbi.nlm.nih.gov/17147458/#:~:text=Reye's%20s....
Biological systems are not designed, but evolved, and evolution ends up selecting systems (which we call "organisms" or "individuals") which are good enough for it to be reproductively successful. In practice that means "low-maintenance" and "energy-efficient". Functional errors and their organism-wide effects slowly accumulate, and although our biology has everything material it needs to fix each and every error[^2], its healing program/intelligence is far from perfect.
[^1]: https://www.youtube.com/watch?v=Sf9I3YORSzM
[^2]: Compare this with a car, for example. If your lights go bust, the car won't grow a new one; you need to change them. But biological organisms have a lot of self-healing capability.
"Blood protein levels predict leading incident diseases and mortality in UK Biobank"
https://www.medrxiv.org/content/10.1101/2023.05.01.23288879v...
( May 03, 2023 ; open, pre-print; not-yet peer-reviewed ; Alzheimer’s dementia included .. )
Abstract:
"The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality, ascertained over 16 years of electronic health linkage in the UK Biobank (N=49,234). We report 3,123 associations between 1,052 protein levels and incident diseases (PBonferroni < 5.4×10−6). Forty-four proteins are indicators of eight or more morbidities. Next, protein-based scores (ProteinScores) are developed using penalised Cox regression. When applied to test sets, eight ProteinScores improve Area Under the Curve (AUC) estimates for the 10-year onset of incident outcomes (PBonferroni < 0.0025) beyond age, sex and additional health and lifestyle covariates. The type 2 diabetes ProteinScore outperforms HbA1c (P = 5.7×10−12) – a clinical marker used to monitor and diagnose type 2 diabetes. A maximal type 2 diabetes model including the ProteinScore, HbA1c and a polygenic risk score has AUC = 0.90 and Precision-Recall AUC = 0.76. These data characterise early proteomic contributions to major age-related disease."
Alzheimer dementia * 10 proteins:
(jpg) https://www.medrxiv.org/content/medrxiv/early/2023/05/03/202...
And you can check the data ( protein * disease ) :
"Our Shiny https://protein-disease-ukb.optima-health.technology app [Username: ukb_disease, Password: shinyappUKB] provides visualisations for sensitivity analyses run across cases over successive years of follow up, allowing for interrogation of individual protein-outcome relationships."
Do you think there will ever be a point where Donanemab or similar drugs will be recommended for all people after a certain age?
If I am thinking of the same medication, doesn't it have pretty nasty side-effects -- 30% chance of brain bleeding, right?
It's tough, because after a certain age, I think it would be worth the risks (in my non-medical professional opinion), but I am not sure if that is how medicine works in practice. I mean, you wouldn't want to give one medicine for a condition that he or she might never end up getting, but you probably also do not want to wait until it's too late.
I am just hoping that we find some kind of treatment in our lifetimes.
More on reflection: Looks like NDST1 has a protective effect, so maybe this is reflecting the shedding going up for some reason. Would need to check what is regulating SPPL3 activity.
I’m wondering, if taking glucosamine supplements could increase the risk of dementia then.
Abstract:
A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.
Does this include autoimmune issues like developing allergies in life?
[2] Zhang, Y.-R. et al. Alzheimers Res. Ther. 14, 130 (2022).
I realize the question is "bro-science", but I'm genuinely interested, perhaps someone educated could expand on it.
I know that androgens can be neuroprotective in the brain.
(I'm partially kidding, most current anabolic steroids aren't selective enough to be safe for any purpose).
So fasting has quite a few cards upon its sleeve and the effect is enormous. But, a therapeutic fasting should be done right and should include water, minerals and vitamins. So it's not quite a full fasting per se, it's more about creating the right conditions for an organism to reboot the broken parts.
But, in my opinion there is more research to be done here to establish whether or not (and to what degree) there is a strong link
https://www.functionhealth.com/whats-included
I work here and it's amazing to watch this space unfold. Lots of great stuff going on in the diagnostic space. Measurement is the first step towards understanding your biochemistry and making changes!
I imagine the testing methods might be your bread & butter, but it's so hard to trust any claims if the results aren't auditable. I think about how these results will matter a lot more to me in 40-50 years, and how unlikely it is for ANY business to last that long.
I personally track a lot of my stuff in a spreadsheet right now but am on a personal hunt for a standard format
Note that, on an individual level, the format of the export really doesn't matter much with the rise of LLMs. I had some past bloodwork results in PDF format, and I was amazed how I could just copy and paste the test results into ChatGPT and it was able to correctly parse and interpret the results. Others may have privacy concerns but I LLMs being able to read and parse a PDF dump of bloodwork is going to be an easy commodity.
Not familiar with that provider, but our core offering tracks this over time. I would recommend comparing the pricing of their tests to the equivalent for us. We are bi-annual for biomarkers that our CMO selected - i.e. some aren't interesting to track in 6 month intervals. You can always add testing at higher frequency if you'd like.
no conflict == no interest
Only when a large clot showed up in lungs did they figure out what was going on.
Week after being on blood thinners and simple programming problems that were taking me weeks to solve were back down to minutes.
Oftentimes it is close to impossible to spot this in a usual bloodwork, but were they able to spot D-dimer anomalies in your case?
Blood clots can be scary. (personal exp). Glad to hear you know why they are happening and how to fix it.
Happy clear-thinking !!!