Proton Pump Inhibitors correlated with AD

[Julie G]

A new paper indicates that the use of PPIs (like Nexium or Prilosec) is correlated with an increase risk of dementia.

Risk of dementia in elderly patients with the use of proton pump inhibitors.
http://www.ncbi.nlm.nih.gov/pubmed/25341874

Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04-1.83] and Alzheimer's disease (HR 1.44, 95 % CI 1.01-2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this finding is of high interest to research on dementia and provides indication for dementia prevention.

[KatieS]

Perhaps, this goes back to role of vitamin absorption with the altered pH from these OTC drugs.I would think that particularly vitamin B12 levels would be lowered.

[bladedmind]

APOE 4/4 here. I have esophageal dysmotility, once-a-month dysphagia (difficulty swallowing), and GERD (heartburn). Been on PPIs for three years. Tapered off in December, 2018 because of dementia risk. GERD is returning now - lung pain and congestion, irritated sinuses, ears, eyes. I know from past experience that this will turn into pneumonias and sinus infections. Those are inflammations also bad in themselves and bad for APOE4s.

I’m facing a choice between lifetime PPI use or elective surgery with risks. I knew about the JAMA study showing a link between PPI and dementia - bad news for APOE4s. So I looked up everything about the association and post it below. The evidence is mixed, I’d say leaning against an association. The mechanism of an association could be reduced nutrient uptake, but I get plenty of good nutrients, vitamins, minerals. If the mechanism is mitochondrial, I’m taking ALC, A Lipoic Acid, CoQ10, magnesium glycinate, benfotiamine, self-injected methyl B-12, some of that for many years.

Similar evidence casts doubt on H2s as well, and they intolerably bother me subjectively (depression, slow thinking) when PPIs don’t.

My university-hospital gastro dept is pushing me to have surgery on my lower esophageal sphincter. Clear up a hiatal hernia and tighten up the LES. I’m a bit worried because this dept will schedule urgent requests for followups on failures of past treatment 2 or 3 months into the future. Also, the surgeon’s nurse says that the surgery is for achalasia; but I quite definitely know that is not the diagnosis (that was an initial diagnosis overturned by further interpretations requested by the first investigator of a senior physician). I got an informal second opinion from another gastro who warned a) that a tightened LES with a weak esophagus could result in daily dysphagia (cure worse than disease) and b) these surgeries can accidentally damage the crucial vagus nerve resulting in disability and in one local case death as the result of elective surgery. All advice welcome. Initial surgery consult is on Jan 31.

Major studies run two for an association, and four against an association. Here are, I think, ALL the refereed studies on the association of PPIs (one on H2s) and dementia. Also, I reference two review articles on possible mechanism of an association (which I can follow superficially, but I lack biomedical training so don’t understand in any depth).

ASSOCIATION PPIS AND DEMENTIA

https://www.ncbi.nlm.nih.gov/pubmed/26882076
JAMA Neurol. 2016 Apr;73(4):410-6. doi: 10.1001/jamaneurol.2015.4791.
Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis.
CONCLUSIONS AND RELEVANCE: The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.

https://www.ncbi.nlm.nih.gov/pubmed/28199356
PLoS One. 2017 Feb 15;12(2):e0171006. doi: 10.1371/journal.pone.0171006. eCollection 2017.
Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan.
Conclusions: An increased risk for dementia was identified among the Asian PPI users. Cumulative PPI use was significantly associated with dementia.

WEAK ASSOCIATION
https://www.ncbi.nlm.nih.gov/pubmed/27903560

WEAK ASSOCIATION OF H2S AND DEMENTIA
https://www.ncbi.nlm.nih.gov/pubmed/17661965


NO ASSOCIATION PPIS AND DEMENTIA

Transcript of podcast discussion by two research teams
https://www.geripal.org/2018/02/ppi-and-dementia.html

https://jamanetwork.com/journals/jamane ... le/2487379
Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis
JAMA Neurol. 2016;73(4):410-416. doi:10.1001/jamaneurol.2015.4791
Conclusions and Relevance The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice.
https://www.alzforum.org/news/research- ... entia-risk
“A similar analysis associated both intermittent and regular PPI use with a lower hazard ratio, 0.82, of being diagnosed with AD. Goldstein and colleagues also analyzed data from people with normal cognition during their first visit separately from those who already had MCI, to see if either group might be more vulnerable to PPIs. They found no increased risk for cognitive decline in either group. Lastly, the authors focused on people 75 and older to more closely mirror the populations tracked in previous studies. Once again, they detected no PPI-associated increase in dementia risk.”

https://www.ncbi.nlm.nih.gov/pubmed/28728964
Gastroenterology. 2017 Oct;153(4):971-979.e4. doi: 10.1053/j.gastro.2017.06.061. Epub 2017 Jul 18.
Association Between Proton Pump Inhibitor Use and Cognitive Function in Women.
“Because of shared clinical indications, we examined associations for H2 receptor antagonists (H2RAs) as a secondary aim….Among individuals who did not use PPIs regularly, duration of H2RA use was associated with poorer cognitive scores”
CONCLUSIONS: In an analysis of data from the Nurses' Health Study II, we did not observe a convincing association between PPI use and cognitive function. Our data do not support the suggestion that PPI use increases dementia risk. Because our primary hypothesis related to PPI use, our findings for H2RAs should be interpreted with caution.

https://www.ncbi.nlm.nih.gov/pubmed/28695906
No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer's Disease.
Am J Gastroenterol. 2017 Dec;112(12):1802-1808. doi: 10.1038/ajg.2017.196. Epub 2017 Jul 11.
No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer's Disease.
CONCLUSIONS: In conclusion, we found no clinically meaningful association between PPI use and risk of AD. The results for longer duration of cumulative use or use with higher doses did not indicate dose-response relationship.

WEAKER NO ASSOCIATION
https://www.ncbi.nlm.nih.gov/pubmed/27903560

https://www.ncbi.nlm.nih.gov/pubmed/26744954

OVERVIEW AND LACK OF CONSENSUS
https://www.alzforum.org/news/research- ... entia-risk
“Besides Goldstein and Haenisch’s work, previous studies have suggested positive, negative, or neutral associations between PPIs and cognitive decline (Nevado-Hurtado et al., 2016; Tai et al., 2017; Booker et al., 2016; Boustani et al., 2007). Last April, a consensus panel of nine international experts in gastroesophageal reflux deemed the results too inconclusive to change their safety recommendations for use of over-the-counter PPIs (Johnson et al., 2017).”
Actually, Johnson 2017 is silent on the issue:
https://www.ncbi.nlm.nih.gov/pubmed/28233274


MECHANISMS OF ACTION

https://www.ncbi.nlm.nih.gov/pubmed/29376492
Curr Med Chem. 2018;25(18):2166-2174. doi: 10.2174/0929867325666180129101049.
Is the Use of Proton-pump Inhibitors a Risk Factor for Alzheimer's Disease? Molecular Mechanisms and Clinical Implications.

https://www.hindawi.com/journals/np/2018/5257285/
Neural Plasticity
Volume 2018, Article ID 5257285, 9 pages
https://doi.org/10.1155/2018/5257285
Review Article
Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences

[LA18]

bladedmind, I had this surgery you’re referring to in 2014, after years of proton pump use for severe laryngopharyngeal reflux. The reflux is definitely better, but I still have some trouble, and I have a suspected adhesion causing dysmotility that may or may not have been there before the surgery, as well as some vagus nerve dysfunction. One thing I would suggest, if you haven’t already done so, it to test for SIBO. I suspect that I’ve had it for years (most of life?) and that this was the root cause of my reflux, or at least what made it so severe. The SIBO got worse after the surgery, and it’s when it peaks now that I have reflux.

The biggest advantage of having the surgery, for me, has been the elimination of a vast array of food sensitivities, potentially caused by the proton pump inhibitor and low levels of hydrochloric acid. I now take hydrochloric acid with meals, which has helped my digestion tremendously and does not cause symptoms (as it would have pre-surgery).

Good luck as you consider your options. I know how difficult LPR can be. I got to the point where my reflux was causing sleep apnea, which was a deciding factor for me in having the surgery. I just wish I knew what I do now so I that would have been able to make a more informed decision, although I can’t say what it would be.

[harpsicon]

Dr. Gundry lists PPI's among his Seven Deadly Dirsupters. While it seems impossible to get in to see him, he allegedly likes "canaries" (as in canaries in the coal mine) who react very badly. Maybe this would get you in to see him - it might be interesting to have his take on this, as he's pretty much against surgery for things like this. fwiw.....

[bladedmind]

Thanks very much for the detailed reports and suggestions, which help. LA18 I've had both a shallow and a deep test of gut bugs and there are no pathogenic organisms (surprising with the PPI but I take probiotics, kombucha, kefir, etc.). I once had severe blastocystis for almost six months, resolved by triple therapy, so I understand how bad that can get. My esophageal dysmotility could be caused by virus, autoimmunity, or many early years of occult GERD. Harpsicon, the problem now is mechanical and can only be fixed mechanically or by shutting down acid with a PPI. I checked what Gundry wrote, and his advice is to try hard to avoid it.

The rule of thumb is surgery only if PPI or H2 can not or should not be taken.

I'm educated enough to dig out the research, but have no training in biomedicine and don't know how to evaluate the quality of the contrasting large-scale studies on PPIs and dementia, or how to evaluate the proposed mechanisms of action for a potential PPI - dementia link in the two survey articles. If the problem is diminished nutrition or remediable mitochondrial insult I might be able to stick to the PPI.

[laurie]

Perhaps, this goes back to role of vitamin absorption with the altered pH from these OTC drugs.I would think that particularly vitamin B12 levels would be lowered.

You are right about B12. My father in law was on a PPI and my husband did some research. PPI's cause B12 malabsorption. My father in law got himself off the PPI but the next time he was hospitalized he was put a back on PPI. My husband had his father take sublingual B12.

In regard to the connection of PPI to dementia, B12 is involved in methylating homocysteine and high levels of homocysteine are associated with arterial sclerosis which leads to a greater risk of vascular dementia. Here is a write up my husband did after his research:
"Vitamin B6, B12, Zinc and Folate Deficiency Increases Homocysteine: Homocysteine is metabolized by enzymes requiring vitamins B6, B12, zinc, and folic acid, a deficiency of any one of these chemicals can cause elevated homocysteine. B12 deficiency (<0.24ng/L) occurs in 3% to 4% of the general population, 15% of the over 65 population and 29% of dementia patients. Levels of both B12 and folic acid have been shown to decrease in cerebral spinal fluid with advancing age."

Here are 2 references Cobalamin is B12 Karnaze D.S., Carmel R.; Low serum cobalamin levels in primary degenerative dementia: do some patients harbor atypical cobalamin deficiency states? Arch Intern Med; 147:429—431 (1987)

Dementia Associated With Vitamin B 12 Deficiency:Presentation of Two Cases and Review of the Literature
Norbert Goebels, M.D.
Michael Soyka, M.D. J Neuropsychiatry Clin Neurosci 12:3, Summer 2000 https://neuro.psychiatryonline.org/doi/ ... p.12.3.389

[bladedmind]

Thank you, Laurie. In 1997 at age 46 I developed brain fog, disabling fatigue, and essential tremors. I was headed for a disability determination and poverty. Part of it was severe allergies, and I went to the famed UK allergist Dr. Leonard McEwen. He treated my allergies, at first with little effect. On one visit, he said, let's try a Methyl B-12 injection. The rest of the day I felt my brain waking up from a long sleep. The next day I bicycled 12 miles jut for fun. No more tremors (also added daily magnesium). The clarity and energy wore off in three weeks. My allergies did get mostly resolved and I have self-injected methyl b-12 on a frequent basis since them.

Everyone should be aware of how essential (methyl) B-12 is to health and thought. You don't need a lot of theory. Just get a Methyl B-12 injection - it' s benign (very-long term use may have a small effect on tumor growth). If you suddenly feel like you're reborn, you need it. If you feel almost nothing, move on. The sublingual off-the-shelf methyl B-12 I am guessing is probably effective - but B12 deteriorates so it's not as certain - and anyway the more lengthy uptake would not be a substitute for the sudden injection test. Don't let anybody tell you that cyanocobalamin is just the same, just as good as, methylcobalamin. Cyanocobalamin does nothing for me, and for others whom I've discussed this with.

[circular]

I have esophageal dysmotility, once-a-month dysphagia (difficulty swallowing), and GERD (heartburn). Been on PPIs for three years. Tapered off in December, 2018 because of dementia risk. GERD is returning now - lung pain and congestion, irritated sinuses, ears, eyes. I know from past experience that this will turn into pneumonias and sinus infections. Those are inflammations also bad in themselves and bad for APOE4s.

I’m facing a choice between lifetime PPI use or elective surgery with risks.

A rather basic question, and your symptoms may be too much to treat through diet alone, but are you eating a lot of GERD inducing foods? I had your symptoms and have avoided PPIs by cutting back on the foods that aggravate it for me. Occasionally when needed before bed I take an aluminum free version of Gaviscon available only from Canada (expensive too), but I don't seem to have the symptoms chronically anymore at all. I know when I ate too much garlic or briny olives for example, and I've learned the amount of such foods that keeps me symptom free. I also elevate the head of my bed somewhat.

FWIW, my mother with AD is on a PPI. I asked her neurologist whether she supported that and in her mind it wasn't an issue because my mother's B12 status is robust, to say the least, and she takes all the usual supplements to keep her homocysteine within range. I've let it be, but if there's another mechanism by which it could feed dementia I'd like to know.

[bladedmind]

Thanks for the suggestion, circular! The GERD is exacerbated by harsh foods but otherwise is constant. It mostly happens silently at night (it burns my lungs, sinuses). I have an adjustable bed frame and that helps a lot. Right now, half a dose of esomeprazole and a much elevated bed work. When I notice some burn, I use the British Gaviscon Advance (unlike US version) which forms the alginate raft . The Gaviscon Advance can be ordered from Amazon or Ebay. You can make it yourself (google for recipe) - I did - but it is messy, not as smooth, not as convenient.

I see the surgeon for consult on Thursday. Part of my problem is that this department, although highly qualified, is overbooked and it takes 8 to 10 weeks to schedule an unanticipated followup. Imagine having unexpected complications following surgery and being told to wait for a consult, never mind any treatment, for two months. Seems to me like a policy that predictably kills a few patients.