Proton pump inhibitors and dementia: what association?

Caetano, Catarina; Veloso, Marta; Borda, Susana

doi:10.1590/1980-5764-DN-2022-0048

Catarina Caetano Correspondence: Catarina Caetano; Email: catarinammcaetano@gmail.com.

conceptualization

data curation

formal analysis

investigation

methodology

project administration

resources

supervision

validation

visualization

writing – original draft

writing – review & editing (lead)

Unidade de Saúde Familiar Delta, Administração Regional de Saúde de Lisboa e Vale do Tejo, Oeiras, Lisboa, Portugal.

https://orcid.org/0000-0003-3325-179X

Marta Veloso

formal analysis

investigation

methodology

validation

writing – original draft

writing – review & editing

Unidade de Saúde Familiar Delta, Administração Regional de Saúde de Lisboa e Vale do Tejo, Oeiras, Lisboa, Portugal.

https://orcid.org/0000-0002-2151-7039

Susana Borda

formal analysis

investigation

methodology

visualization

writing – original draft

writing – review & editing

Unidade de Saúde Familiar Delta, Administração Regional de Saúde de Lisboa e Vale do Tejo, Oeiras, Lisboa, Portugal.

https://orcid.org/0000-0002-9641-7083

Correspondence: Catarina Caetano; Email: catarinammcaetano@gmail.com.

Disclosure: The authors report no conflicts of interest.

Author, year	Type of study	Sample size	Intervention	Outcome	Results	Conclusion	LE
Moayyedi et al.²⁷27 Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682-91.e2. https://doi.org/10.1053/j.gastro.2019.05.056 https://doi.org/10.1053/j.gastro.2019.05... , 2019	Multicenter double-blind randomized controlled trial	17,598	Pantoprazole 40 mg vs. placebo in patients with atherosclerotic disease	Secondary: Dementia diagnosis in the follow-up period (3 years)	OR=1.2; 95%CI (0.81–1.78) (p=0.36)	No association	I

	LE	I	I	II	I	I	I	II		II	II
	Conclusion	Increased risk	Increased risk	Risk reduction	No association	No association	No association	Increased risk		No association	No association
Observational studies	Results	ACD: HR=1.38; 95%CI (1.04–1.8); AD: HR=1.44; 95%CI (1.01–2.06)	HR=1.44; 95%CI (1.36–1.52) (p<0.001)	From normal cognition: HR=0.78; 95%CI (0.66–0.93) (p=0.005)Progression from MCI to Dementia: HR=0.82; 95%CI (0.69–0.98) (p=0.03)	ACD: OR=1.13 (p=0.67)AD: OR=1.11 (p=0.77). Cumulative doses of: 365 TSDDs, 1,095 TSDDs and 1,825 TSDDs: HRs without statistical significance.	Mean score differences from 0.00 to −0.06 points for periods of PPI use between 1 to 14 years. p≥0.84	HR=0.99, 95%CI (0.70–1.37)	Dementia diagnosis: aSR=1.21;95%CI (1.16–1.27). Use of anti-dementia drugs: aSR=1.38 95%CI (1.28–1.48)		Elderly PPI users vs. non-users: difference of −1.22 points, 95%CI (−3.73–1.29) Individuals 46-67 years old PPI users vs. non-users: difference of 0.94 points, 95%CI (−1.63–3.50)	Prolonged use of PPIs: HR=0.99, 95%CI (0.93–1.17) Intermittent use of PPIs: HR=0.91, 95%CI (0.76–1.09)
	Outcome	Diagnosis of all-cause dementia or Alzheimer's disease	Dementia diagnosis	Diagnosis of LBD (Lewy Bodies Dementia)Dementia from normal cognition or diagnosis of dementia in patients with LBD.	Diagnosis of all-cause dementia or Alzheimer's disease	Neurocognitive assessment performance	Dementia diagnosis	Dementia diagnosis or prescription of anti-dementia drugs		Neurocognitive assessment performance	Dementia diagnosis
	Intervention	PPIs use	PPIs use	PPIs use	PPIs use (cumulative dose)	PPIs use	Cumulative dose PPIs vs. H2 blockers	PPIs use		PPIs use	PPIs use
	Sample	3,076	73,679	10,486	3,484	13,864	70,529	1,000,000		7,878	10,533
	Type of study	Prospective cohort	Prospective cohort	Retrospective cohort	Prospective cohort	Prospective cohort	Prospective cohort	Retrospective cohort		Prospective cohort	Retrospective cohort
	Author, Year	Haenisch et al.¹⁴14 Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265(5):419-28. https://doi.org/10.1007/s00406-014-0554-0 https://doi.org/10.1007/s00406-014-0554-... , 2015	Gomm et al.¹⁵15 Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-6. https://doi.org/10.1001/jamaneurol.2015.4791 https://doi.org/10.1001/jamaneurol.2015.... , 2016	Goldstein et al.³⁵35 Goldstein FC, Steenland K, Zhao L, Wharton W, Levey AI, Hajjar I. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc. 2017;65(9):1969-74. https://doi.org/10.1111/jgs.14956 https://doi.org/10.1111/jgs.14956... , 2017	Gray et al.²⁸28 Lochhead P, Hagan K, Joshi AD, Khalili H, Nguyen LH, Grodstein F, et al. Association between proton pump inhibitor use and cognitive function in women. Gastroenterology. 2017;153(4):971-9.e4. https://doi.org/10.1053/j.gastro.2017.06.061 https://doi.org/10.1053/j.gastro.2017.06... , 2017	Lochhead et al.²⁷27 Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682-91.e2. https://doi.org/10.1053/j.gastro.2019.05.056 https://doi.org/10.1053/j.gastro.2019.05... , 2017	Hwang et al.³⁰30 Hwang IC, Chang J, Park SM. A nationwide population-based cohort study of dementia risk among acid suppressant users. Am J Geriatr Psychiatry. 2018;26(11):1175-83. https://doi.org/10.1016/j.jagp.2018.06.002 https://doi.org/10.1016/j.jagp.2018.06.0... , 2018	Park et al.³¹31 Park SK, Baek YH, Pratt N, Ellett LL, Shin JY. The uncertainty of the association between proton pump inhibitor use and the risk of dementia: prescription sequence symmetry analysis using a Korean healthcare database between 2002 and 2013. Drug Saf. 2018;41(6):615-24. https://doi.org/10.1007/s40264-018-0638-2 https://doi.org/10.1007/s40264-018-0638-... , 2018		Wod et al.²⁹29 Wod M, Hallas J, Andersen K, Rodríguez LAG, Christensen K, Gaist D. Lack of association between proton pump inhibitor use and cognitive decline. Clin Gastroenterol Hepatol. 2018;16(5):681-9. https://doi.org/10.1016/j.cgh.2018.01.034 https://doi.org/10.1016/j.cgh.2018.01.03... , 2018	Huang et al.³⁷37 Huang ST, Tseng LY, Chen LK, Peng LN, Hsiao FY. Does long-term proton pump inhibitor use increase risk of dementia? Not really! Results of the group-based trajectory analysis. Clin Pharmacol Ther. 2019;106(3):616-22. https://doi.org/10.1002/cpt.1430 https://doi.org/10.1002/cpt.1430... , 2019
Observational studies	LE	II	II	II	II	II	II	II	II	II	II
	Conclusion	No association	Increased risk	Increased risk	Risk reduction	Increased risk	No association	No association	Risk reduction	No association	No association
	Results	IRR=1.01;95%CI (0.96–1.06)	OR=1.55 (p<0.001)	aHR=1.42;95%CI (1.07–1.84) Association between cumulative dose and risk of dementia with statistical significance (p-trend<0.001)	HR=0.67, 95%CI (0.65–0.67)(p<0.01)	AD: aOR=1.06;95%CI (0.93–1.21)nAD: aOR=1.20, 95%CI (1.05–1.37)(p=0.007). AD for high dose PPI: aOR=1.20; 95%CI (0.91–1.61)nAD for high dose PPI: aOR=0.95, 95%CI (0.74–1.22)	aHR=0.72;95%CI (0.51–1.03)	aOR=1,0; 95%CI (0,40–2,73)	OR=0.93, CI95% (0.90–0.97)(p=0.0008)	aOR=1.01;95%CI (0.97–1.06)	AD: aOR=0.88; 95%CI (0.80–0.97)VV: aOR=1.18, 95%CI (1.04–1.33)
	Outcome	Dementia diagnosis	Dementia diagnosis or prescription of anti-dementia drugs	Dementia diagnosis	Dementia diagnosis	Diagnosis of Alzheimer's disease or non-Alzheimer dementia	Dementia diagnosis	Dementia diagnosis	Dementia diagnosis	Alzheimer's Disease Diagnosis	Development of Alzheimer's Disease or Vascular Dementia
	Intervention	PPIs use	PPIs use	PPIs use (cumulative dose)	PPIs use	PPIs use	PPIs use (and H2 blockers)	Continuous PPIs’ use	PPIs use	PPIs use (cumulative dose)	PPIs use
	Sample	304,753	23,656	62,574	315,078	135,722	92,773	7,8 billion	23,912 (1:1)	353,576 (1:4)	41,029
	Type of study	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Cross-sectional	Case control	Case control	Case control
	Author, Year	Park et al.³⁶36 Park SK, Nam JH, Lee H, Chung H, Lee EK, Shin JY. Beyond uncertainty: negative findings for the association between the use of proton pump inhibitors and risk of dementia. J Gastroenterol Hepatol. 2019;34(12):2135-43. https://doi.org/10.1111/jgh.14745 https://doi.org/10.1111/jgh.14745... , 2019	Welu et al.³²32 Welu J, Metzger J, Bebensee S, Ahrendt A, Vasek M. Proton pump inhibitor use and risk of dementia in the veteran population. Fed Pract. 2019;36(Suppl 4):S27-S31. PMID: 31296980, 2019	Chen et al.³³33 Chen LY, Lin HJ, Wu WT, Chen YC, Chen CL, Kao J, et al. Clinical use of acid suppressants and risk of dementia in the elderly: a pharmaco-epidemiological cohort study. Int J Environ Res Public Health. 2020;17(21):8271. https://doi.org/10.3390/ijerph17218271 https://doi.org/10.3390/ijerph17218271... , 2020	Cooksey et al.³⁴34 Cooksey R, Kennedy J, Dennis MS, Escott-Price V, Lyons RA, Seaborne M, et al. Proton pump inhibitors and dementia risk: evidence from a cohort study using linked routinely collected national health data in Wales, UK. PLoS One. 2020;15(9):e0237676. https://doi.org/10.1371/journal.pone.0237676 https://doi.org/10.1371/journal.pone.023... , 2020	Torres-Bondia et al.¹⁶16 Torres-Bondia F, Dakterzada F, Galván L, Buti M, Besanson G, Gill E, et al. Proton pump inhibitors and the risk of Alzheimer's disease and non-Alzheimer's dementias. Sci Rep. 2020;10(1):21046. https://doi.org/10.1038/s41598-020-78199-0 https://doi.org/10.1038/s41598-020-78199... , 2020	Wu et a.l³⁸38 Wu CL, Lei WY, Wang JS, Lin CE, Chen CL, Wen SH. Acid suppressants use and the risk of dementia: a population-based propensity score-matched cohort study. PLoS One. 2020;15(11):e0242975. https://doi.org/10.1371/journal.pone.0242975 https://doi.org/10.1371/journal.pone.024... , 2020	Ma et al.⁴²42 Ma C, Shaheen AA, Congly SE, Andrews CN, Moayyedi P, Forbes N. Interpreting reported risks associated with use of proton pump inhibitors: residual confounding in a 10-year analysis of national ambulatory data. Gastroenterology. 2020;158(3):780-2.e3. https://doi.org/10.1053/j.gastro.2019.10.023 https://doi.org/10.1053/j.gastro.2019.10... , 2020	Booker et al.⁴¹41 Booker A, Jacob LE, Rapp M, Bohlken J, Kostev K. Risk factors for dementia diagnosis in German primary care practices. Int Psychogeriatr. 2016;28(7):1059-65. https://doi.org/10.1017/S1041610215002082 https://doi.org/10.1017/S104161021500208... , 2016	Taipale et al.⁴⁰40 Taipale H, Tolppanen AM, Tiihonen M, Tanskanen A, Tiihonen J, Hartikainen S. No association between proton pump inhibitor use and risk of Alzheimer's disease. Am J Gastroenterol. 2017;112(12):1802-8. https://doi.org/10.1038/ajg.2017.196 https://doi.org/10.1038/ajg.2017.196... , 2017	Imfeld et al.³⁹39 Imfeld P, Bodmer M, Jick SS, Meier CR. Proton pump inhibitor use and risk of developing Alzheimer's disease or vascular dementia: a case-control analysis. Drug Saf. 2018;41(12):1387-96. https://doi.org/10.1007/s40264-018-0704-9 https://doi.org/10.1007/s40264-018-0704-... , 2018

Systematic reviews
Author, Year	Type of study	Sample	Studies included	Results	Conclusion	LE
Batchelor et al.¹³13 Batchelor R, Gilmartin JFM, Kemp W, Hopper I, Liew D. Dementia, cognitive impairment and proton pump inhibitor therapy: a systematic review. J Gastroenterol Hepatol. 2017;32(8):1426-35. https://doi.org/10.1111/jgh.13750 https://doi.org/10.1111/jgh.13750... , 2017	Systematic reviews	101,616	One experimental study and 10 observational studies (4 cohort, 1 case-control, 1 cross-sectional, 1 case series, and 3 case reports)	No meta-analysis	Increased risk	II
Hussain et al.¹⁷17 Hussain S, Singh A, Zameer S, Jamali MC, Baxi H, Rahman SO, et al. No association between proton pump inhibitors use and risk of dementia: evidence from a meta-analysis. J Gastroenterol Hepatol. 2020;35(1):19-28. https://doi.org/10.1111/jgh.14789 https://doi.org/10.1111/jgh.14789... , 2020	Systematic review and meta-analysis	618,911	12 observational studies (8 cohort and 4 case-control)	RR=1.05, 95%CI 0.96–1.15	No association	I
Li et al.¹²12 Li M, Luo Z, Yu S, Tang Z. Proton pump inhibitor use and risk of dementia: systematic review and meta-analysis. Medicine (Baltimore). 2019;98(7):e14422. https://doi.org/10.1097/MD.0000000000014422 https://doi.org/10.1097/MD.0000000000014... , 2019	Systematic review and meta-analysis	106,599	6 cohort studies	RR=1.23; 95%CI 0.90–1.67Follow-up < 5 years: RR=1.62, 95%CI 1.40–1.86 Follow-up > 5years: RR=0.98, 95%CI 0.75–1.27	No association	I
Song et al.⁴⁷47 Song YQ, Li Y, Zhang SL, Gao J, Feng SY. Proton pump inhibitor use does not increase dementia and Alzheimer's disease risk: an updated meta-analysis of published studies involving 642305 patients. PLoS One. 2019;14(7):e0219213. https://doi.org/10.1371/journal.pone.0219213 https://doi.org/10.1371/journal.pone.021... , 2019	Systematic review and meta-analysis	642,305	10 observational studies (5 cohort, 4 case control, and 1 cross-sectional)	ACD: HR=1.04, 95%CI 0.92–1.15 AD: HR 0.96, 95%CI 0.83–1.09	No association	I
Zhang et al.⁴⁴44 Zhang Y, Liang M, Sun C, Song EJ, Cheng C, Shi T, et al. Proton pump inhibitors use and dementia risk: a meta-analysis of cohort studies. Eur J Clin Pharmacol. 2020;76(2):139-47. https://doi.org/10.1007/s00228-019-02753-7 https://doi.org/10.1007/s00228-019-02753... , 2020	Systematic review and meta-analysis	166,146	6 cohort studies	HR=1.29, 95%CI 1.12–1.49	Increased risk	I
Desai et al.⁴⁶46 Desai M, Nutalapati V, Srinivasan S, Fathallah J, Dasari C, Chandrasekhar VT, et al. Proton pump inhibitors do not increase the risk of dementia: a systematic review and meta-analysis of prospective studies. Dis Esophagus. 2020;33(10):doaa041. https://doi.org/10.1093/dote/doaa041 https://doi.org/10.1093/dote/doaa041... , 2020	Systematic review and meta-analysis	308,249	One experimental study and 5 prospective observational	ACD: HR=1.16, 95%CI 0.86–1.47	No association	I
Khan et al.⁴⁵45 Khan MA, Yuan Y, Iqbal U, Kamal S, Khan M, Khan Z, et al. No association linking short-term proton pump inhibitor use to dementia: systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2020;115(5):671-8. https://doi.org/10.14309/ajg.0000000000000500 https://doi.org/10.14309/ajg.00000000000... , 2020	Systematic review and meta-analysis	642,949	11 observational studies (6 cohort, 4 case control, and 1 cross-sectional)	ACD: HR=1.10; OR=1.03.AD: HR=1.06; OR=0.96	No association	I
Zhang et al.⁴⁸48 Zhang Y, Zhan J, Bao Q, Lu J, Tan L. Possible dementia risk of proton pump inhibitors and H2 receptor blockers use in the treatment of Helicobacter pylori: a meta-analysis study. Med Hypotheses. 2020;144:109989. https://doi.org/10.1016/j.mehy.2020.109989 https://doi.org/10.1016/j.mehy.2020.1099... , 2020	Systematic review and meta-analysis	371,951	10 observational studies	OR=0.87; 95%CI 0.62–1.22	No association	II

[1] Correspondence: Catarina Caetano; Email: catarinammcaetano@gmail.com.

Brasil

Brasil

Proton pump inhibitors and dementia: what association?

Inibidores da bomba de protões e demência: que associação?

ABSTRACT.

Objective:

Methods:

Results:

Conclusions: