. 2023 Oct 31;101(18):e1771-e1778.

doi: 10.1212/WNL.0000000000207747. Epub 2023 Aug 9.

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study

Carin A Northuis¹, Elizabeth J Bell¹, Pamela L Lutsey¹, Kristen M George¹, Rebecca F Gottesman¹, Tom H Mosley¹, Eric A Whitsel¹, Kamakshi Lakshminarayan²

Affiliations

¹ From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill.
² From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill. laksh004@umn.edu.

PMID: 37558503
PMCID: PMC10634644
DOI: 10.1212/WNL.0000000000207747

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study

Carin A Northuis et al. Neurology. 2023.

. 2023 Oct 31;101(18):e1771-e1778.

doi: 10.1212/WNL.0000000000207747. Epub 2023 Aug 9.

Authors

Carin A Northuis¹, Elizabeth J Bell¹, Pamela L Lutsey¹, Kristen M George¹, Rebecca F Gottesman¹, Tom H Mosley¹, Eric A Whitsel¹, Kamakshi Lakshminarayan²

Affiliations

¹ From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill.
² From the University of Minnesota (C.A.N., P.L.L., K.L.), Minneapolis; Optum (E.J.B.), Minneapolis, MN; University of California, Davis (K.M.G.); National Institute of Neurological Disorders and Stroke (R.F.G.), Washington, DC; University of Mississippi Medical Center (T.H.M.), Jackson; and University of North Carolina (E.A.W.), Chapel Hill. laksh004@umn.edu.

PMID: 37558503
PMCID: PMC10634644
DOI: 10.1212/WNL.0000000000207747

Erratum in

Corrections to Received Date Information.
[No authors listed] [No authors listed] Neurology. 2024 Jul 9;103(1):e209596. doi: 10.1212/WNL.0000000000209596. Epub 2024 Jun 3. Neurology. 2024. PMID: 38830175 Free PMC article. No abstract available.

Abstract

Background and objectives: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study.

Methods: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use.

Results: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use.

Discussion: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia.

Classification of evidence: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.

Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

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Conflict of interest statement

C.A. Northuis reports no disclosures relevant to the manuscript; E.J. Bell is employed by Optum, and she has received funding Novartis, Incyte, AstraZeneca, EMD Serono, Sandoz, Celgene, and Pfizer; P.L. Lutsey receives NIH funding; K.M. George reports no disclosures relevant to the manuscript; R.F. Gottesman is supported by the NIH intramural program; T.H. Mosley receives NIH funding; E.A. Whitsel reports no disclosures relevant to the manuscript; K. Lakshminarayan receives NIH funding. Go to Neurology.org/N for full disclosures.

Figures

**Figure. Flowchart of Participants in the Atherosclerosis Risk in Communities Study, 2011–2017**
APOE4 = Apolipoprotein E4; BMI = body mass index.

See this image and copyright information in PMC

Comment in

Dauertherapie mit PPI steigert Demenzrisiko.
Duning T. Duning T. MMW Fortschr Med. 2024 Mar;166(4):35. doi: 10.1007/s15006-024-3700-2. MMW Fortschr Med. 2024. PMID: 38453855 Review. German. No abstract available.

References

1. Maes ML, Fixen DR, Linnebur SA. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence. Ther Adv Drug Saf. 2017;8(9):273-297. - PMC - PubMed
1. Jaynes M, Kumar AB. The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf. 2019;10:2042098618809927. - PMC - PubMed
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1. Rotman SR, Bishop TF. Proton pump inhibitor use in the U.S. ambulatory setting, 2002-2009. PLoS One. 2013;8(2):e56060. - PMC - PubMed

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Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study

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