Can Common Heartburn Drugs Raise Risk for Dementia?

A widely used class of medications that treat acid reflux has been tied to dementia. In the February 15 JAMA Neurology, scientists led by Britta Haenisch, German Center for Neurodegenerative Diseases, Bonn, report that elderly people who regularly used proton pump inhibitors (PPIs) had a 44 percent greater risk of developing dementia than people who didn’t use these drugs. Although correlative, the results suggest that avoiding these medications could help prevent cognitive decline, the authors claim.

“This is an interesting study and certainly an attention-grabber,” said Ralph Nixon, New York University School of Medicine. While the paper may make people worry about being on PPIs, they will need to balance this degree of dementia risk with a need to lower risks associated with acid-related disorders, which may be substantial, he told Alzforum.

PPIs such as omeprazole, pantoprazole, and lansoprazole treat gastroesophageal reflux disease and peptic ulcers—some would say far more often than necessary (Heidelbaugh et al., 2012). Studies estimate that 3 to 5 percent of the population over age 65 takes PPIs, which are among the top-selling drugs worldwide (Qato et al., 2008; Kaufman et al., 2002). PPIs are available by prescription and over-the-counter, and their use is growing, especially in older people (Hollingworth et al., 2010). 

These drugs bind and inhibit the cellular gastric proton pump that supplies the stomach with acid. Found in all cells, several types of proton pump use energy from ATP to transport ions across membranes. An example is the vacuolar-type adenosine triphosphatase (V-ATPase). It acidifies lysosomes so that they can degrade unwanted proteins. PPIs weakly block those lysosomal pumps (Mattsson et al., 1991). In rodents, these drugs have been found to cross the blood-brain barrier, leading some scientists to wonder if they affect cells in the brain (Cheng et al., 2002). 

Analyzing data from the longitudinal AgeCoDe study, which follows more than 3,000 people age 75 or older in primary care settings in Germany, Haenisch and colleagues had previously found that those taking PPIs were at a 38 percent greater risk of developing dementia 18 months later (Haenisch et al., 2014). 

To expand on their finding, co-first authors Willy Gomm and Klaus von Holt examined longitudinal medical records from the massive database of the public health insurer Allgemeine Ortskrankenkassen, which was founded in 1884 and insures a third of the German population. The researchers tracked people aged 75 years and older who were living dementia-free from 2004 to 2011. Of 73,679 people, 2,950 had taken PPIs long-term, while 70,729 took none. After adjusting for factors such as age, gender, depression, diabetes, and stroke, people on PPIs were 44 percent likelier to develop various types of dementia, including Alzheimer’s and vascular dementia. Another 66,008 people in the database used PPIs occasionally; their risk rose by 16 percent.

An accompanying editorial puts these numbers in perspective. A 44 percent increase in dementia among PPI users in the United States could translate to 10,000 additional new cases every year among people aged 75 to 84, assuming about 3 percent of them took these acid reflux meds, noted Lewis Kuller, University of Pittsburgh. Kuller cautioned that the link may be coincidental. General drug use in this population may signal poor health overall, and the reasons that lead people to take PPIs could make also them more vulnerable to dementia. The association needs to be validated in large cohorts and tested in case-control studies, he wrote. Nevertheless, Kuller acknowledges that a causal link is plausible.

Haenisch and colleagues point out that PPI use can lead to vitamin B12 deficiency, which has been associated with cognitive decline (Lam et al., 2013). The PPI lansoprazole has been reported to augment processing of the amyloid precursor protein by β- and γ-secretases in mice, which would imply increased amyloid production in the brain, though another study reported that lansoprazole acts as an LXR agonist, which would imply amyloid reduction (Badiola et al., 2013; Cronican et al., 2010). 

Researchers in Iran proposed years ago that PPIs cross the blood-brain barrier and reduce the acidity of microglial lysosomes by blocking their V-ATPase pumps, making them less able to break down fibrillar brain amyloid (Fallahzadeh et al., 2010). Michael Heneka, German Center for Neurodegenerative Disease, Bonn, commented that there is no evidence to suggest treatment with PPIs makes microglial lysosomes less acidic in vivo.

Nixon, who studies neuronal and glial lysosomes in AD, noted that PPIs enter the brain poorly even at high doses, and that they have much lower affinity for the microglial V-ATPase than they do for the gastric proton pump. Unpublished data from Nixon’s lab suggests that even if a PPI got into the brain, cells there would compensate by upregulating V-ATPase expression. Frederick Maxfield, Weill Cornell Medical College, New York, agreed that PPIs are unlikely to reach sufficiently high concentrations in the brain to affect microglial lysosomes. However, he and Nixon said the potential link is worth investigating further. Even a small decrement in lysosomal function could be meaningful if the lysosome is already compromised, Nixon said.

Other mechanisms could explain the association with dementia. For one, Peter Scott, University of Michigan, Ann Arbor, proposed that since lansoprazole inhibits p-glycoprotein, which may help shuttle Aβ from the brain to the blood, amyloid might accumulate as a result (Pauli-Magnus et al., 2001). Scott agreed that further clinical studies are warranted (see full comment below).—Gwyneth Dickey Zakaib

Comments

  1. This is very interesting work, and the apparent role of PPIs in dementia is worthy of further investigation. We have studied [18F]lansoprazole and its derivatives as high-affinity PET radiotracers for tau neurofibriliary tangles (see Fawaz et al., 2014). However, we know that while derivatives have proven useful for imaging tau, at radiotracer doses in rats, monkeys, and humans, lansoprazole does not cross the blood-brain barrier (BBB) to enter the CNS because it is a P-glycoprotein (Pgp) substrate/inhibitor (see Pauli-Magnus et al., 2001). P-glycoprotein helps maintain the integrity of the BBB by pumping molecules that enter endothelial cells back into the blood. At the higher doses used for routine PPI therapy, lansoprazole could block Pgp activity. Since Pgp deficiency at the BBB is thought to increase amyloid-β deposition (see Cirrito et al., 2005), the proposed link between lansoprazole and dementia could be increased accumulation of amyloid as a result of Pgp inhibition. It remains to be determined whether all Pgp inhibitors and/or PPIs are correlated with increased dementia and if this is a medical class side effect, or whether it is specific to the PPIs tested in the present work. Either way, further clinical studies investigating the preliminary findings that connect PPIs to dementia are warranted.

    References:

    Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, Sherman P, Quesada CA, Hockley BG, Kilbourn MR, Albin RL, Frey KA, Scott PJ. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chem Neurosci. 2014 Aug 20;5(8):718-30. Epub 2014 Jun 16 PubMed.

    Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):551-7. PubMed.

    Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Nov;115(11):3285-90. PubMed.

    View all comments by Peter Scott

  2. This study by Gomm et al. examined a very large sample of nearly 74,000 patients in a large German administrative claims database and found higher risk of dementia among those with regular proton-pump inhibitor (PPI) use than in those not using PPIs at all over a period of up to seven years. The database study results confirm previous analyses in a smaller, complementary, clinic-based study with more direct and detailed observations. Given the numbers of older adults on long-term PPI therapy (2-3 percent in the United States as suggested by Kuller’s commentary), understanding any cognitive risks involved is critical.

    That being said, the study has some limitations worth pointing out: 1) The authors assessed associations between PPI use and a coded billing claim of dementia, not a clinical diagnosis of dementia. Much dementia is clinically unrecognized, or at least uncoded, and there are likely false positives as well. 2) A second issue is that PPIs may be more often used long-term to treat gastrointestinal complications from NSAID use in secondary prevention for cardiovascular disease. Because cardiovascular risk factors and cardiovascular disease increase risk for dementia, this means that long-term PPI use probably occurs more frequently among patients with higher underlying risk for dementia. The authors attempt to counter this issue by adjusting for ischemic heart disease and stroke diagnoses, but the related diagnostic codes likely also involve some misclassification, so confounding of this sort may only be partially resolved. 3) The analyses excluded participants based on their entire PPI use trajectory over many years, specifically dropping those with intermittent use throughout follow-up, which relies on very strong assumptions about how confounding factors are related to prior PPI use. Some of these issues might be resolved in large cohort studies that have both clinically validated dementia diagnoses and linkable prescription dispensing claims. Using such data, more sophisticated modelling approaches could be used to appropriately censor patients when they stop taking PPIs regularly.

    The study's findings (along with the earlier clinical study) are certainly concerning. Whether or not the methodological limitations are first-, second-, or third-order issues remains to be resolved. Hopefully, other investigators will work to confirm these findings in other databases with appropriate study designs and analytic tools.

    View all comments by John Jackson

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References

Paper Citations

  1. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012 Jul;5(4):219-32. PubMed.
  2. Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA. 2008 Dec 24;300(24):2867-78. PubMed.
  3. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002 Jan 16;287(3):337-44. PubMed.
  4. Hollingworth S, Duncan EL, Martin JH. Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemiol Drug Saf. 2010 Oct;19(10):1019-24. PubMed.
  5. Mattsson JP, Väänänen K, Wallmark B, Lorentzon P. Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases. Biochim Biophys Acta. 1991 Jun 18;1065(2):261-8. PubMed.
  6. Cheng FC, Ho YF, Hung LC, Chen CF, Tsai TH. Determination and pharmacokinetic profile of omeprazole in rat blood, brain and bile by microdialysis and high-performance liquid chromatography. J Chromatogr A. 2002 Mar 8;949(1-2):35-42. PubMed.
  7. Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, Brettschneider C, König HH, Werle J, Weyerer S, Luppa M, Riedel-Heller SG, Fuchs A, Pentzek M, Weeg D, Bickel H, Broich K, Jessen F, Maier W, Scherer M. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2014 Oct 24; PubMed.
  8. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013 Dec 11;310(22):2435-42. PubMed.
  9. Badiola N, Alcalde V, Pujol A, Münter LM, Multhaup G, Lleó A, Coma M, Soler-López M, Aloy P. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8(3):e58837. Epub 2013 Mar 8 PubMed.
  11. Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease?. J Clin Pharm Ther. 2010 Apr;35(2):125-6. PubMed.
  12. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):551-7. PubMed.

Further Reading

Papers

  1. Hamzat H, Sun H, Ford JC, Macleod J, Soiza RL, Mangoni AA. Inappropriate prescribing of proton pump inhibitors in older patients: effects of an educational strategy. Drugs Aging. 2012 Aug 1;29(8):681-90. PubMed.
  2. Sodhi RK, Singh N. Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet. PLoS One. 2013;8(7):e70487. Print 2013 PubMed.
  3. Booker A, Jacob LE, Rapp M, Bohlken J, Kostev K. Risk factors for dementia diagnosis in German primary care practices. Int Psychogeriatr. 2016 Jul;28(7):1059-65. Epub 2016 Jan 8 PubMed.
  4. Akter S, Hassan MR, Shahriar M, Akter N, Abbas MG, Bhuiyan MA. Cognitive impact after short-term exposure to different proton pump inhibitors: assessment using CANTAB software. Alzheimers Res Ther. 2015 Dec 27;7(1):79. PubMed.
  5. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2015 Dec 30; PubMed.

Primary Papers

  1. Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, Doblhammer G, Haenisch B. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016 Apr 1;73(4):410-6. PubMed.
  2. Kuller LH. Do Proton Pump Inhibitors Increase the Risk of Dementia?. JAMA Neurol. 2016 Apr 1;73(4):379-81. PubMed.

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