Opinion
EDITORIAL
Do Proton Pump Inhibitors Increase the Risk of Dementia? Lewis H. Kuller, MD, DrPH
In 2015, the German Study on Aging, Cognition and Dementia in Primary Care Patients reported that among 2911 persons 75 years of age or older, the use of proton pump inhibitors (PPIs) was associated with an increased risk of dementia (hazard ratio [HR], 1.33 [95% CI, 1.04-1.83) and an increased risk of Alzheimer disease (HR, 1.44 [95% CI, 1.01-2.06]).1 The study by Gomm et al2 used a large German insurance database to link PPI use and subsequent incidence of dementia using both inpatient and outpatient medical records. They have found a similar increase in the risk of dementia among PPI users (HR, 1.44 [95% CI, 1.36-1.52]).2 Determining the relatively low prevalence of PPI use among older individuals required a very large database with available follow-up information about incidence of dementia to evaluate the association of PPI use and dementia. The use of an administrative database restricts the quality of the diagnosis of dementia and types of dementia. The availability of their prior study with a smaller sample size but a more detailed evaluation of dementia enhances the possible validity of their conclusions. Proton pump inhibitors were introduced in the 1980s for the treatment of acid-related disorders of the upper gastrointestinal tract, including “heartburn,” peptic ulcers, and gastrointestinal reflux disorders.3 The drugs are available in the United States, both as prescription and nonprescripRelated article tion drugs. Several studies have reported that 2% to 3% of the population older than 65 years of age were receiving long-term PPI therapy.4-6 In the National Health and Nutrition Examination Survey, use of PPIs increased from 3.4% to 7.0% among men and from 4.8% to 8.5% among women from 1999-2000 to 2011-2013.7 The incidence of dementia and the prevalence of brain pathology (eg, amyloid deposition, vascular disease, and brain atrophy) among older individuals are very high.8,9 Even a relatively small risk of dementia can result in a substantial increased risk for older individuals and an increase in the number of patients with dementia in the population. For example, a 1.4-fold increased risk of dementia, as suggested by these 2 German studies, would increase the estimated incidence rate of dementia from 6.0% per year8 to approximately 8.4% per year. There are approximately 13 500 000 people 75 to 84 years of age. If 3% were receiving PPIs (n = 400 000), then this could result in an increase of about 10 000 new cases of incident dementia per year just in this age group (eg, 24 000 new cases of incident dementia per year at 6% vs 33 000 new cases of incident dementia per year at 8.4%). Whether PPIs actually cause an increase in the risk of dementia is therefore an important question requiring further evaluation. First, there is some biological plausibility to the hyjamaneurology.com
pothesis that PPIs can cross the blood-brain barrier.10 They may increase both production11 and degradation12 of amyloid, at least in animal models, and bind to tau.10 There is also evidence of reduced levels of B12 and other nutrients among PPI users that could possibly relate to an increased risk of dementia.13 It is also possible, however, that the reported association of PPI use and dementia is not causal. First, older individuals often take many drugs, and the number of drugs taken may be a function of the extent of disease and comorbidities. Polypharmacy was a risk factor for dementia in the German studies1,2 already mentioned but did not preclude the association of PPI use with dementia. However, specific drug(s) may be associated with both PPI use and dementia.14 The higher prevalence of comorbidities and diseases will also increase contact with physicians in the medical community and increase the likelihood of the risk of dementia (the Berksonian bias). The determinants of both the diseases and the factors related to the use of PPIs may also be related to the risk of dementia. For example, in the Women’s Health Initiative, participants who consumed PPIs had poorer health, had a higher prevalence of angina and arthritis, and, in the German study, had depression.6 In the Women’s Health Initiative, there was also a positive association of obesity and PPI use, and there is probably a higher prevalence of PPI use in relationship to both cigarette smoking and alcohol consumption. These factors may also contribute to the risk of dementia. There is also a very strong inverse association of risk of dementia and education. Differences in distribution of education for gastrointestinal acid diseases and use of PPIs may account for the association of PPI use and risk of dementia. Further determinants of whether PPIs are causal for dementia requires validation in large cohorts and probably in welldesigned case-control studies with good measures of PPI use (especially long-term use), covariates, and especially methods to measure incidence of dementia. Smaller studies could also evaluate whether PPIs are associated with specific brain neuropathology, especially amyloid deposition, tau, and neurodegeneration. Gomm et al2 have provided an important and interesting challenge to evaluate the possible association of the use of PPIs and the risk of dementia. This is a very important issue given the very high prevalence of pharmacological drugs’ longterm use in elderly populations that have a very high risk of dementia. An important issue raised by this study2 and similar studies of drugs that may increase risk of dementia is whether a careful evaluation of cognitive changes and/or neuropathology should be a component of the evaluation of drugs that are widely used among the elderly.15 (Reprinted) JAMA Neurology Published online February 15, 2016
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 02/15/2016
E1
Opinion Editorial
ARTICLE INFORMATION Author Affiliation: Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania. Corresponding Author: Lewis H. Kuller, MD, DrPH, Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, 130 N Bellefield Ave, Room 550, Pittsburgh, PA 15261 ([email protected]). Published Online: February 15, 2016. doi:10.1001/jamaneurol.2015.4931.
10. Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB. Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2010;19(2):573-589.
5. 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;287(3):337344.
11. Badiola N, Alcalde V, Pujol A, et al. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8(3): e58837.
REFERENCES
6. Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med. 2010;170(9):765-771.
1. Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265(5):419-428.
7. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999-2012. JAMA. 2015;314(17):1818-1831.
2. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis [published online February 15, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791.
8. Kuller LH, Lopez OL, Becker JT, Chang Y, Newman AB. Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study [published October 28, 2015]. Alzheimers Dement. doi:10.1016/j.jalz.2015.08.165.
Conflict of Interest Disclosures: None reported.
3. McQuaid KR, Laine L. Early heartburn relief with proton pump inhibitors: a systematic review and meta-analysis of clinical trials. Clin Gastroenterol Hepatol. 2005;3(6):553-563.
E2
4. 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;300(24):2867-2878.
12. Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther. 2010;35(2): 125-126. 13. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. 14. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014;349:g5205. 15. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.
9. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol. 2010;67(1):114-121.
JAMA Neurology Published online February 15, 2016 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 02/15/2016
jamaneurology.com
EDITORIAL
Do Proton Pump Inhibitors Increase the Risk of Dementia? Lewis H. Kuller, MD, DrPH
In 2015, the German Study on Aging, Cognition and Dementia in Primary Care Patients reported that among 2911 persons 75 years of age or older, the use of proton pump inhibitors (PPIs) was associated with an increased risk of dementia (hazard ratio [HR], 1.33 [95% CI, 1.04-1.83) and an increased risk of Alzheimer disease (HR, 1.44 [95% CI, 1.01-2.06]).1 The study by Gomm et al2 used a large German insurance database to link PPI use and subsequent incidence of dementia using both inpatient and outpatient medical records. They have found a similar increase in the risk of dementia among PPI users (HR, 1.44 [95% CI, 1.36-1.52]).2 Determining the relatively low prevalence of PPI use among older individuals required a very large database with available follow-up information about incidence of dementia to evaluate the association of PPI use and dementia. The use of an administrative database restricts the quality of the diagnosis of dementia and types of dementia. The availability of their prior study with a smaller sample size but a more detailed evaluation of dementia enhances the possible validity of their conclusions. Proton pump inhibitors were introduced in the 1980s for the treatment of acid-related disorders of the upper gastrointestinal tract, including “heartburn,” peptic ulcers, and gastrointestinal reflux disorders.3 The drugs are available in the United States, both as prescription and nonprescripRelated article tion drugs. Several studies have reported that 2% to 3% of the population older than 65 years of age were receiving long-term PPI therapy.4-6 In the National Health and Nutrition Examination Survey, use of PPIs increased from 3.4% to 7.0% among men and from 4.8% to 8.5% among women from 1999-2000 to 2011-2013.7 The incidence of dementia and the prevalence of brain pathology (eg, amyloid deposition, vascular disease, and brain atrophy) among older individuals are very high.8,9 Even a relatively small risk of dementia can result in a substantial increased risk for older individuals and an increase in the number of patients with dementia in the population. For example, a 1.4-fold increased risk of dementia, as suggested by these 2 German studies, would increase the estimated incidence rate of dementia from 6.0% per year8 to approximately 8.4% per year. There are approximately 13 500 000 people 75 to 84 years of age. If 3% were receiving PPIs (n = 400 000), then this could result in an increase of about 10 000 new cases of incident dementia per year just in this age group (eg, 24 000 new cases of incident dementia per year at 6% vs 33 000 new cases of incident dementia per year at 8.4%). Whether PPIs actually cause an increase in the risk of dementia is therefore an important question requiring further evaluation. First, there is some biological plausibility to the hyjamaneurology.com
pothesis that PPIs can cross the blood-brain barrier.10 They may increase both production11 and degradation12 of amyloid, at least in animal models, and bind to tau.10 There is also evidence of reduced levels of B12 and other nutrients among PPI users that could possibly relate to an increased risk of dementia.13 It is also possible, however, that the reported association of PPI use and dementia is not causal. First, older individuals often take many drugs, and the number of drugs taken may be a function of the extent of disease and comorbidities. Polypharmacy was a risk factor for dementia in the German studies1,2 already mentioned but did not preclude the association of PPI use with dementia. However, specific drug(s) may be associated with both PPI use and dementia.14 The higher prevalence of comorbidities and diseases will also increase contact with physicians in the medical community and increase the likelihood of the risk of dementia (the Berksonian bias). The determinants of both the diseases and the factors related to the use of PPIs may also be related to the risk of dementia. For example, in the Women’s Health Initiative, participants who consumed PPIs had poorer health, had a higher prevalence of angina and arthritis, and, in the German study, had depression.6 In the Women’s Health Initiative, there was also a positive association of obesity and PPI use, and there is probably a higher prevalence of PPI use in relationship to both cigarette smoking and alcohol consumption. These factors may also contribute to the risk of dementia. There is also a very strong inverse association of risk of dementia and education. Differences in distribution of education for gastrointestinal acid diseases and use of PPIs may account for the association of PPI use and risk of dementia. Further determinants of whether PPIs are causal for dementia requires validation in large cohorts and probably in welldesigned case-control studies with good measures of PPI use (especially long-term use), covariates, and especially methods to measure incidence of dementia. Smaller studies could also evaluate whether PPIs are associated with specific brain neuropathology, especially amyloid deposition, tau, and neurodegeneration. Gomm et al2 have provided an important and interesting challenge to evaluate the possible association of the use of PPIs and the risk of dementia. This is a very important issue given the very high prevalence of pharmacological drugs’ longterm use in elderly populations that have a very high risk of dementia. An important issue raised by this study2 and similar studies of drugs that may increase risk of dementia is whether a careful evaluation of cognitive changes and/or neuropathology should be a component of the evaluation of drugs that are widely used among the elderly.15 (Reprinted) JAMA Neurology Published online February 15, 2016
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 02/15/2016
E1
Opinion Editorial
ARTICLE INFORMATION Author Affiliation: Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania. Corresponding Author: Lewis H. Kuller, MD, DrPH, Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, 130 N Bellefield Ave, Room 550, Pittsburgh, PA 15261 ([email protected]). Published Online: February 15, 2016. doi:10.1001/jamaneurol.2015.4931.
10. Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB. Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2010;19(2):573-589.
5. 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;287(3):337344.
11. Badiola N, Alcalde V, Pujol A, et al. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8(3): e58837.
REFERENCES
6. Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med. 2010;170(9):765-771.
1. Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265(5):419-428.
7. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999-2012. JAMA. 2015;314(17):1818-1831.
2. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis [published online February 15, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791.
8. Kuller LH, Lopez OL, Becker JT, Chang Y, Newman AB. Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study [published October 28, 2015]. Alzheimers Dement. doi:10.1016/j.jalz.2015.08.165.
Conflict of Interest Disclosures: None reported.
3. McQuaid KR, Laine L. Early heartburn relief with proton pump inhibitors: a systematic review and meta-analysis of clinical trials. Clin Gastroenterol Hepatol. 2005;3(6):553-563.
E2
4. 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;300(24):2867-2878.
12. Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther. 2010;35(2): 125-126. 13. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. 14. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014;349:g5205. 15. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.
9. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol. 2010;67(1):114-121.
JAMA Neurology Published online February 15, 2016 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pittsburgh User on 02/15/2016
jamaneurology.com
![[Do proton pump inhibitors increase the risk of myocardial infarction?].](/assets/img/hold.png)
