Understanding Studies that Link the Long-term Use of PPI's with Dementia in Context

Why Does the Habitual Use of PPI’s Increase the Risk for Dementia?

Evelyn Smith

M.S. in Library Science, University of North Texas (2012)

This week’s headlines that correlate the use of proton pump inhibitors with an increased risk for dementia should serve as a warning against reading medical reports in isolation and out of context, even though the information stems from a peer-reviewed JAMA Neurology article. 

Gomm, W., von Holt, K., Thomé, F.  (2016, February 16).  Association of proton pump inhibitors with risk of dementia:  A pharmacoepidemiological claims data analysis.  JAMA Neurology. doi:10.1001/jamaneurol.2015.4791. [Abstract only; published Online first].  Retrieved from http://archneur.jamanetwork.com/article.aspx?articleid=2487379

After conducting a longitudinal, cohort study using observational data from Germany’s statutory health insurer from 2004 to 2011, researchers found that out of the 73,679 participants free of Alzheimer’s at baseline, those regularly receiving proton pump inhibitor medications had a “significantly increased risk of incident dementia” (Gomm, 2016, February 16, Abstract only).

However, reading this abstract does not tell the whole story since the data only links the incidence of dementia with the habitual use of PPI’s--not the reasons why the dementia occurs:  One of which is a vitamin B₁₂ deficiency (Jameson, 2013, December 13), although taking PPI’s also meddles with beta and tau amyloid plaque levels (Badiola, 2013).  Of course, making permanent life style changes, such as losing access weight, might also decrease the need for taking PPI’s as well as decrease the risk for dementia.

See also:

Link between indigestion drugs and dementia ‘inconclusive’.  (2016, February 16).  NHS Choices.  Retrieved from http://www.nhs.uk/news/2016/02February/Pages/Link-between-indigestion-drugs-and-dementia-inconclusive.aspx

A peer-reviewed German study sensationalized in The Daily Mail and The Daily Telegraph  that associated a 44 percent higher risk of dementia with the habitual, long term use of PPI’s is accurate, although this risk might have other plausible causes (Link, 2016, February 16, para. 4-5).  Adults age 75 and older taking PPI’s ordinarily are in poorer health and are thus taking more medications than their peers not suffering from acid reflux (Link, 2016, February 16, para. 6).  The NHS therefore recommends that those currently taking PPI’s should not stop taking them without consulting a physician since this could acerbate their digestive problems (Link, 2016, February 16, para. 7). 

Adhering to a healthy [Mediterranean or DASH] diet, watching one’s weight, regularly exercising [30 minutes four or five days a week], consuming alcohol in moderation, not smoking, and controlling blood pressure all reduce the risk for dementia, according to the NHS (Link, 2016, February 16, para. 35).

The NHS article provides links to the original JAMA Neurology article as well as to the Daily Mail and Daily Telegraph articles.  All the same, while reassuring, the British give few details, so keep reading.

Locke, Tim. (2016, February 17).  Proton pump inhibitors linked to dementia.  Heartburn/GORD Health Center.  WebMD.  Retrieved from http://www.webmd.boots.com/heartburn-gord/news/20160217/proton-pump-inhibitors-linked-to-dementia

A new study has again confirmed a link between proton pump inhibitors taken for heartburn and acid reflux with an increased risk of Alzheimer’s; however, it does not determine whether PPI’s directly cause dementia in senior adults (Locke, 2016, February 17, para. 1-2). The study which looked at the medical data on 73,679 Germans age 75 and older between 2004 and 2011 found that those who used a PPI for at least 18 months had a “significantly higher risk” of dementia than those not taking these medications.

Researchers also took into account additional risk factors, like diabetes, depression, stroke, and being prescribed additional drugs, but they didn’t consider the participants’ educational levels, so critics claim that the study has only established a statistical link between PPI’s and Alzheimer’s (Locke, 2016, February 17, para. 6-9  & 14 & 16). The use of PPI’s is also higher among smokers and the obese, which are also risk factors for dementia.  Moreover, PPI users are ordinarily in poorer health and thus at greater risk for diabetes and stroke (Locke, 2016, February 17, para. 17-18).

The more education one has, the less likely he or she is to succumb to dementia because presumably this knowledge should translate into better lifestyle habits.  All the same, most older and middle-aged adults can point to numerous university-educated, individuals, who died from Alzheimer’s.  Moreover, only a randomized trial could conclusively prove that taking PPI’s for a year and a half or more drastically increases an older adult’s chances of developing dementia.

Molchan, Susan. (2016, February 16).  Our psychiatrist-reviewer analyzes news about proton pump inhibitors and dementia risk.  Heathewsreview.  Retrieved from http://www.healthnewsreview.org/2016/02/our-psychiatrist-reviewer-analyzes-news-about-proton-pump-inhibitors-dementia-risk/

Susan Molchan points out that an association between the regular use of PPI’s and a “significant” increase for the  risk of dementia doesn’t indicate cause and effect since only a randomized, controlled trial can prove more than a statistical correlation.  Moreover, she cautions that the abstract itself overstates the study’s findings (Molchan, 2016, February 16, para. 4-5).

Even so, the use of PPI’s by adults over age 75 might increase their risk of dementia for various reasons:

PPI’s cross the blood-brain barrier;

They lower vitamin B12 levels, which if too low can cause dementia;

They interact with amyloid and tau protein.

Nevertheless, the habitual use of PPI’s might in itself might not raise the risk of dementia since older adults often take lots of drugs for lots of different health conditions, such as cardiovascular disease, that also increase the risk of dementia (Molchan, 2016, February 16, para. 6). 

Molchan then goes on to note that the Food and Drug Administration has long warned that the use of PPI’s is associated with an increased risk of fractures, unhealthy magnesium and calcium levels, and severe diarrheal infections.  She also notes that physicians routinely over prescribe PPI’s  (Molchan, 2016, February 16, 7-8).

But, the statistical link is still troubling:

Proton pump inhibitors may be associated with increased dementia risk. (2016, February 15).  Neuroscience News.  Retrieved from http://neurosciencenews.com/proton-pump-inhibitor-dementia-3663/

Researchers affiliated with the German Center for Neurodegenerative Diseases in Bonn, using data culled from patient diagnoses and drug prescriptions found a statistical link between the regular use of proton pump inhibitors (at least one PPI prescription in each quarter of an 18-month interval) and an increased risk of dementia (Proton pump, 2016, February 15, para. 3).  The study examined the records of 218,493 Germans aged 75 and older, identifying 29,510 patients who eventually developed dementia (Proton pump, 2016, February 15, para. 4).  Regular users of PPI’s had a 44 percent increased risk of dementia, although the authors were only able to integrate some other risk factors in their analysis (Proton pump, 2016, February 15, para. 6-7).  A copy of the abstract follows Neuroscience News’ synopsis of the JAMA Neurology article.

Fortunately, some commentary delves a little deeper, noting that research associates regularly taking PPI’s with vitamin B ₁₂ deficiency, and they also warn that diet and weight control might contribute both the reasons for acid reflux and dementia.

Thomson, Dennis. (2016, February 15).  Popular heartburn drugs linked to risk of dementia.  Healthday.  CBSNews.  Retrieved from http://www.cbsnews.com/news/heartburn-drugs-ppi-prilosec-nexium-prevacid-risk-of-dementia/

German researchers have found that adults aged 75 and older who regularly take proton pump inhibitors, including Prilosec, Nexium, and Prevacid, had a 44 percent increased risk of dementia compared with those who didn’t use PPI’s, although correlation in this longitudinal study doesn’t necessarily mean causation (Thomson, 2016, February 15, para. 1-3).

These results are surprising enough that one leading expert on aging plans to share these results with older patients taking PPI’s since they may change the levels of amyloid beta and tau protein association with Alzheimer’s as well as lead to vitamin B12 deficiency, which previous researchers have long linked with cognitive decline (Thomson, 2016, February 15, para. 7 & 15). Some experts, however, caution that since researchers as yet do not know why the aging brain deteriorates, those taking PPI’s should not be too concerned since the researchers failed to control for diet and weight as risk factors (Thomson, 2016, February 15, para. 24-30).  

Nevertheless, those patients who want to “ease off” taking PPI’s can reduce excess acid and prevent acid reflux by eating smaller meals, cutting out caffeine and chocolate, and sitting upright for two or three hours after eating (Thomson, 2016, February 15, para. 22).

All the same, the PPI lansoprazole does enhance the production of beta amyloid plaque in lab rats:

Badiola N., Alcalde, V., and Pujol, A., et al. (2013). The proton-pump inhibitor Lansoprazole enhances amyloid beta production. PLoS ONE, 8(3), e58837. doi:10.1371/journal.pone.0058837.  [Open Access].  Retrieved from http://bio.davidson.edu/courses/genomics/2013/Systems.pdf

In cell models, the proton-pump inhibitor lansoprazole enhances Ab37, Ab40 and Ab42 production as well as lowering Ab38 levels in amyloid cell models. Additionally, acute lansoprazole treatment promotes higher Ab-40 levels I the brains of wild and transgenic mice.

Moreover, a previous, much smaller German study did control for such risk factors as ApoE status, taking additional medications, depression, diabetes, and cardiovascular disease.

Haenish, B., Von Holt, K., and Wiese, B. (2015, August).  Risk of dementia in elderly patients with the use of proton pump inhibitors.  European Archives of Psychiatry and Clinical Neuroscience, 265(5), pp. 419-28.  doi: 10.1007/s00406-014-0554-0.  [Abstract only].  Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25341874

Assessing the association between the use of PPI’s and dementia in older adults, the German Study on Aging, Cognition and Dementia in Primary Care Patients analyzed 3,327 community dwelling adults 75 years of age and older, noting that participants receiving a PPI medication had a “significantly increased risk” of dementia compared with non-users after considering factors such as age, gender, ApoE status, additional medications, depression, diabetes, ischemic heart disease, and stroke (Haenish, 2015, August, Abstract, p. 419).

Furthermore, previous American studies emphasize that the use of PPI’s leads to the inability to effectively absorb vitamin B₁₂:

Jameson, R., Lam, M. P. H., and Schneider, J. L., et al. (2013, December 13).  Proton pump inhibitor and histamine ₂ receptor antagonist use and vitamin B₁₂ deficiency.  JAMA, 310(22), pp. 2435-2442).  [Full text]. doi: 10.1001/jama.2013.280490.  Retrieved from http://jama.jamanetwork.com/article.aspx?articleid=1788456

Proton pump inhibitors and histamine ₂ receptor antagonists not only suppress the production of gastric acid, but their regular use potentially leads to “malabsorption of vitamin B₁₂, according to an examination of electronic pharmacy, laboratory, and diagnostic records of 25,956 Northern California patients ensured through Kaiser Permanente.  Among patients diagnosed with incidental vitamin B₁₂ deficiency, 12 percent received two or more years of PPI prescriptions, and 4.2 percent received two or more years of H₂RA’s, and 83.8 percent didn’t take either PPI or H2RA prescriptions (Jameson, 2013, December 13, Abstract, para. 1-5, p. 2435).  “Left untreated, vitamin B₁₂ deficiency can lead to dementia, neurological damage, and other complications, which may be irreversible” (Jameson, 2013, December 13, Abstract, Conclusion, para. 7, p. 2435).

A New York Times article as well as an Alzheimer Research Foundation article also note the increased risk for vitamin B12 deficiency as pointed out by an earlier American study:

See also:

Saint Louis, Catherine. (2013, December 10).  Acid-suppressing drugs linked to vitamin B12 deficiency.  Well.  New York Times.  Retrieved from http://well.blogs.nytimes.com/2013/12/10/acid-suppressing-drugs-linked-to-vitamin-b12-deficiency/?_r=0

Individuals of all ages who use proton-pump inhibitors and histamine ₂ receptor antagonists two years or longer increase their risk for vitamin B₁₂ deficiency, which, in turn, can sometimes lead to anemia, neurological problems, or dementia (Saint Louis, 2013, December 10, para. 1-2). 

Thus, those taking these medications should be routinely screened for vitamin B₁₂ deficiency, according to Douglas A. Corley, who along with his colleagues at Kaiser Permanente examined the pharmaceutical and diagnostic records of 25,956 Californians  diagnosed with Vitamin B ₁₂ deficiency between 1997 and 2011 (Saint Louis, 2013, December 10, para. 3 & 5).  Researchers found that patients who took PPI’s for more than two years were 65 percent more likely to be deficient in vitamin B₁₂ as well as those who took higher dosages of PPI’s (Saint Louis, 2013, December 10, para. 6).

The benefits of PPI’s need to be weighed against their risks, including bone fractures, pneumonia, severe diarrhea, and vitamin B₁₂ deficiency.  Other factors, such as adhering to a vegetarian diet might also explain a vitamin B₁₂ deficiency (Saint Louis, 2013, December 10, para. 13-14). Additionally, when researchers analyzed 20 randomly-selected charts of PPI-using patients, they discovered that 25 percent had anemia and 15 percent suffered from memory loss.  Accordingly, physicians need to counsel patients on the overuse and abuse of PPI’s (Saint Louis, 2013, December 10, para. 15-16).

Netzer, W. J. (reviewer).  (2016). How heart burn drugs may lead to memory problems.  The Fisher Center for Alzheimer’s Research Foundation.  Retrieved from https://www.alzinfo.org/articles/how-heartburn-drugs-may-lead-to-memory-problems/

The use of both over the counter and prescription proton pump inhibitors used to treat gastro-esophageal reflux disease and stomach and intestinal ulcers and histamine ₂ receptor antagonists leads to an increased risk of low vitamin B₁₂ levels, which, in turn, correlates with an increased risk of dementia.  When low vitamin B₁₂ deficiency goes untreated, it can lead to irreversible dementia, neurological damage, and anemia (Netzer, 2016, para. 1-3). 

Four in ten Americans suffer from acid reflux, and thus taking these drugs might put them at additional risk for vitamin B₁₂ deficiency.  Adults over age 50 are particularly at risk for this deficiency because they have problems absorbing vitamin B₁₂ found in fish, meat, and dairy products, so taking vitamin B₁₂ supplements may be necessary (Netzer, 2016, para. 4 & 10).

These findings come from a survey of 25,956 Kaiser Permanente patients diagnosed with vitamin B12 deficiency, 12 percent of whom had been taking PPI’s for at least two years compared with 7.2 percent who weren’t taking any acid reflux medications. Although higher dosages of PPI’s put patients more at risk, this increased risk decreases after older adults stop taking PPI’s (Netzer, 2016, para. 5 & 6).  Thus, physicians should prescribe the lowest workable dosages for PPI’s as well as discussing the risk associated with them (Netzer, 2016, para. 7-8). 

Folic acid, Vitamin B6 and Vitamin B12 help keep “brain areas critical for memory and thinking in good health” particularly in those seniors already diagnosed with mild cognitive impairment (Netzer, 2016, para. 9).

Thus, physicians should monitor the levels of vitamin B12 in their patients who are taking either over-the-counter or prescription PPI’s.  Additionally, users of PPI’s age 50 and older should 1) try to improve the conditions that put them on PPI’s in the first place, better controlling their weight and diet, so they no longer need to take them, and 2) routinely take a vitamin supplement and recognize the signs of vitamin B₁₂ deficiency:

Nazario, Brunilda. (2015, July 23).  Vitamin B12 deficiency.  WebMD., pp. 1-2.  Retrieved from http://www.webmd.com/food-recipes/guide/vitamin-b12-deficiency-symptoms-causes

• Weakness, tiredness, or lightheadedness
• Heart palpitations and shortness of breath
• Pale skin
• A smooth tongue
• Constipation, diarrhea, a loss of appetite, or gas
• Nerve problems like numbness or tingling, muscle weakness, and problems walking
• Vision loss
• Mental problems like depression, memory loss, or behavioral changes

(Nazario, 2015, July 23, p. 2)

All of which means that older adults who use PPI's should take a multivitamin that contains vitamin B12 or a vitamin B12 supplement (Nazario, 2015, July 23, p. 2). 

Finally, the public should be weaned away from the idea that simply popping a pill is the cure for anything since maintaining a healthy mind and body often calls for lifestyle changes.