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Proton pump inhibitors (heartburn meds) linked with increased risk of dementia (wiley.com)
85 points by Urgo 28 days ago | hide | past | web | favorite | 40 comments



From abstract: "Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis."

This is classical A causes B and B causes C, so A leads to C which is something we have had before with amyloid plaques. This does not tell us this is false, but really just a link and nothing more.

Some beautiful day, we will fully understand the cause of dementia. Today is not that day.


Somewhat tangentially, do you have an opinion on whether PPIs cause dementia, regardless of what the mechanism may be?

Reason I ask is that I've been taking them daily for years to control GERD, so I'm wondering if I'm frying my brain. But I'm not really qualified to understand the intricacies of this kind of research.

Even further tangent: seems like they may also cause acute kidney injury. Yaaaay. I guess everything is a tradeoff. https://www.ncbi.nlm.nih.gov/pubmed/30779194


Sorry but no, I do not have an opinion on that.


I agree. The conclusions in the abstract are not warranted by the experiments. It's hard to imagine a situation where in silico docking experiments lead to a clinical conclusion such as "This call (sic) for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis."


> This is classical A causes B and B causes C, so A leads to C

Another one is salt intake raises blood pressure and high blood pressure causes heart attacks.

The reality is more complicated: https://www.thelancet.com/journals/lancet/article/PIIS0140-6...


Somewhat tangential, but I have a story about acid reflux that I think is worth sharing for anyone who is in a similar boat.

Basically, I was having reflux symptoms minus the heartburn. Lots of throat issues, digestive issues, coughing, etc. My doctor looked everything over and concluded that reflux was the most likely cause and we did a treatment of PPIs for a few weeks.

The PPI didn't help, but by the time the treatment was over we were in the middle of this pandemic so I couldn't go back into the doc for a next step.

Luckily a few weeks later I randomly stumbled into a fix. One day I noticed the symptoms were gone and when I thought about it I realized I had started taking an additional allergy medication a few days prior. So it seems that instead of reflux I had postnasal drip.

To be fair to the doctor he did mention postnasal drip as a possibility, but reflux was deemed as more likely because I was already on allergy meds and the symptoms were very reflux-y.

Obviously if you have reflux like symptoms, see a doc, but I thought my experience was worth sharing for anyone in a similar boat. It's fairly simple to try new allergy meds and see if that's the root cause. In my case adding a steroidal nasal spray into the mix was what helped. And it resolved the issue in a couple days, whereas trying out PPIs was a two month long experiment of continued suffering. (Side note: not all steroidal nasal sprays are created equal. I had previously tried Flonase which did nothing for me.)


Thanks for sharing your experience.

Note that I am not a doctor, but I have my own theories that I want to share: post-nasal drip results in more swallowing, which triggers more acid production, which in turn results in more of the stomach content (ie. acid) getting back into the esophagus, hence GERD.

Acid that reaches high in the throat, for instance while lying down, will likely cause burning that will also result in post-nasal drip or similar symptoms. See the problem here? One issue amplifies the other. That's why once you get into a bad state it's difficult to return to some normality.

Also, other digestive system issues, such as IBS (irritable bowel syndrome), depending on the type and rootcause, will result in GERD. For instance, if you are often bloated, your digestive system may be slowed down significantly, which means there's no place for the stomach content to move into. Hence, more of the content may return into your esophagus.

The good news is that if there's no other underlying condition, these issues can be kept in check with lifestyle changes: diet and exercise (walking seems to be helping a lot; no surprise there, since humans have evolved to walk long distances; also no surprise that a sedentary lifestyle has so many negative effects on us).

Edit: there also seems to be a link between GERD and asthma, in the sense that acid reaching the airways, including lungs, may cause asthma.


A very timely comment for me. I’ve been experiencing some throat/coughing issues for a couple months now. Doctor doesn’t think it was covid, but who knows. I did, however, stop taking a nasal steroid I had been using for a few years right around the same time the symptoms started. Maybe I’ll start using it again and see what happens. Thanks.


Anedcote from me: I took Omeprazole for years and had to stop when I entered USMC bootcamp. All stomach issues disappeared when I started exercising and eating right. That was over 10 years ago and to this day my stomach is fine. I've kept up the habit of eating well and exercising mildly.

TL;DR change your eating habits and exercise before trying to solve everything with a drug


Yeah obviously lifestyle should be a first course of action. In my case, no lifestyles changes helped. Which makes sense, since the underlying cause appears to have been allergies.


which allergy medications worked best for you? I also have the same issues.


Right now Xyzal plus generic Nasacort. WARNING: "As with any medicine, you should ask your doctor or healthcare provider about using other allergy medications in conjunction with Nasacort."

Nasacort or similar is also nice to have around when switching allergy medications, since a lot of the 2nd gen stuff takes a week or more to reach full effect. So you can use it for those first two weeks on a new medication to help cover the gap.


Which spray worked for you?


Generic version of Nasacort.


Stomach is known to kill stuff before they become harmful to us. If PPIs let more things through... well that makes sense.

Specifically: - https://www.statnews.com/2020/05/06/researchers-show-herpes-...

There are more relating to opportunistic fungal, bacterial, and so on. Relating to the mechanism of increased susceptibility to infection may be related to our stomach's part in naturally being an infection load regulator through its acid, in combination with our hydration gradient providing for our saliva in (that tract). Someone please credit me in the future if they win a nobel prize.


This is just anecdotal, but I've had problems with heartburn for years and am having great succes with betaine hcl + pepsin supplements. This actually increases stomach acid. That + dietary changes almost completely cleared my problems. Just throwing it out there. YMMV.


Same here. I guess my issue was inadequate stomach acid, not excess...


What dietary changes?

Idk if what I have is heartburn but the past 2 months or so I have been waking up to horrific stomach aches. Taking a round of Prilosec seems to have helped it. But I may want to backpedal on it given this news.


Typically people are asked to avoid acidic foods (tomatoes, citrus), raw onions, chocolate, caffeine, sodas, peppermint and high fat foods.


I don't get why high fat foods are lumped in here. I've started avoiding all the others you mentioned, and my reflux has stopped, but I'm on a ketogenic diet that's very high in fat.


Some foods loosen the sphincter making it easier to get reflux. Like eating a slice of pepperoni pizza. My dietitian said each individual is different so you need to determine what works or doesn't works for you.


I think the most effective dietary advice in the world is this:

Change one thing for two weeks, and see if it gets better or worse.

You can fix a surprisingly wide range of problems by changing your diet in a slow, methodical way.


Along these lines, not drinking excessively with meals can help, since you're not dilluting your stomach acid.


While there are some eyebrow-raising studies suggesting the correlation between PPI use and dementia, it is far from settled science. There are conflicting studies, and some meta-analyses suggest no association. Of course, studies saying drugs are safe don't make the news.

"No association between proton pump inhibitor use and risk of dementia: Evidence from a meta‐analysis" Journal of Gastroenterology and Hepatology (Jan 2020, https://doi.org/10.1111/jgh.14789)

"Dementia, cognitive impairment and proton pump inhibitor therapy: A systematic review" Journal of Gastroenterology and Hepatology (August 2017, https://doi.org/10.1111/jgh.13750)

"Risk factors for dementia diagnosis in German primary care practices" International Psychogeriatrics (July 2016, https://doi.org/10.1017/S1041610215002082)

From the last article: "The use of statins (OR: 0.94; 0.90–0.99), proton-pump inhibitors (PPI) (0.93; 0.90–0.97), and antihypertensive drugs (0.96, 0.94–0.99) were associated with a decreased risk of developing dementia."


This article is stating a correlation but the reason they did this is that there is molecular evidence for cholinergic pathways in the body, and drugs which are anti-cholinergic, causing Alzheimer's because of this system being integral to the development of Alzheimer's disease.

The whole reason they decided to do this correlational study - and other studies like it - is because they have evidence that this cholinergic system plays a part in developing Alzheimers. Then, to back up that molecular theory and evidence, they're looking at correlations that the drugs that target this system have in developing Alzheimers. Sure enough things like how much one uses Diphenhydramine (active ingredient in benadryl and the same can be said for other allergy medications that are anti-cholinergic) shows that increased use has a direct correlation with increased risks of developing Alzheimer's disease.

Many studies on these anti-cholinergic drugs shows this correlation, they also have an understanding of the molecular basis of why, however in addition they also show that drugs that target this system in certain ways help reduce the symptoms of the disease.

Because of this, the evidence points to medications that fall into this "anti-cholinergic" or "slighly anti-cholinergic" drug category - allergy medications (diphenhydramine, loratadine) some PPI and others - might also amplify the chances of getting the disease.

There seems to be a lot of evidence pointing to this, and while its still an emerging area I'm confused as to how you are stating that this system and these drugs that interact with it, which has a lot of evidence that it is part of the disease pathophysiology, are weak on evidence?

What is your background and the experience you have to be able to state what you just said?

Here is some background on this system and its implications with Alzheimer's :

https://www.medscape.com/viewarticle/900644

"The Cholinergic System in the Pathophysiology and Treatment of Alzheimer's Disease"

"Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. "


> There seems to be a lot of evidence pointing to this, and while its still an emerging area I'm confused as to how you are stating that this system and these drugs that interact with it, which has a lot of evidence that it is part of the disease pathophysiology, are weak on evidence?

Because there is evidence to the contrary, which I posted. Some even from a few months ago.

My goal is to bring balance to the discussion. Too often we see only the headlines that something might cause ${DREADED_DISEASE}, but ignore studies saying the opposite. It's a play on fear.

> What is your background and the experience you have to be able to state what you just said?

This is needlessly confrontational.

My background: PhD in chemistry. While relatively unrelated, I do know how to read and find follow-up research. My interest also stems from taking a PPI, and hearing only the one side from concerned family members.


And untreated chronic heartburn has a fairly strong link to cancer. And some of the better non-PPI drugs, like ranitidine were just pulled by the FDA for impurities. Then, famotidine is in short supply because of some study that it might treat COVID-19. Yikes.


I remember aluminum and particularly aluminum hydroxide as a heartburn drug was linked to dementia before. Nothing happened, because proofing causation seems close too impossible ruling out other confounders. I wonder without understanding all of the reasoning if this is any different? Can you prove sth. without an intervention?


I don't know, but where I live, it's basically impossible to buy these anymore.


Interesting study linked from this one: "Cognitive impact after short-term exposure to different proton pump inhibitors" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696341/


A good next study would to see if the study participants' decline reversed after being removed from the drugs.


I had severe acidity issue and ended up in a condition called Barrett's esophagus . Doctor advised me to Omeprazole 40mg life long. After taking it for 6 months, i started following gluten free diet and all my gerd symptoms gone away. After 3 years, my Barrett's esophagus condition also reversed.


i dont see it mentioned here, but for occasional acid reflux, a tsp of baking soda in water works great


Came here to say that. It’s dirt cheap and probably has less interactions and side effects too.


Off-topic: Maybe it's just me, and this is not important in the least, but I have been always slightly irritated by the use of the term "proton" in chemistry which they use to denote the (positive) hydrogen ion. Two reasons: unlike "electron", the term "proton" belongs in physics exclusively and not chemistry which only deals with point-like nuclei carrying mass plus an electric charge, and the electron cloud; the other reason was that just like many - if not most - chemical elements, hydrogen has several isotopes, and it is conceivable that at least some of the ions may have a neutron in its nucleus.


> the use of the term "proton" in chemistry which they use to denote the (positive) hydrogen ion

H+/K+ ATPase is a proton pump, not a hydrogen ion pump. It evolved to pump protons, and mostly pumps protons.

> the term "proton" belongs in physics exclusively and not chemistry which only deals with point-like nuclei carrying mass plus an electric charge, and the electron cloud

Lots of biological machinery fails with heavy hydrogen isotopes, including some proton pumps [1]. This is why heavy water is poisonous [2].

[1] https://tbiomed.biomedcentral.com/articles/10.1186/1742-4682...

[2] https://en.m.wikipedia.org/wiki/Heavy_water


I agree with the GP. Biology is chemistry, and the hydrogen electron shell is what's important in chemistry, not the nucleus. If the proton didn't act as a hydrogen nucleus, we wouldn't use the term PPI at all.

Heavy water being (slightly) toxic doesn't have any bearing on the larger point.


> the hydrogen electron shell is what's important in chemistry, not the nucleus

H+/K+ ATPase is literally a case of a proton pump that pumps protons. It’s in a class of proton pumps that pump far less efficiently, biologically-meaningfully less efficiently, with heavier isotopes. The nuclear structure is relevant.

“Hydrogen pumps” would be inaccurate. “Hydrogen ion pumps”, while practically fine, would be less precise.

General use of the term proton for hydrogen ions is debatable. But this is ironically a case where it isn’t.


>hydrogen electron shell is what's important in chemistry, not the nucleus

The kinetic isotope effect would like to have a word with you.


Yes, there are extremely obscure corner cases in nature. The larger point, once again, stands.




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