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Cumulative Use of Proton Pump Inhibitors and Risk of Dementia
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This study evaluated whether the current and cumulative use of proton pump inhibitors (PPIs) are associated with a higher risk of incident dementia. Compared with no PPI use, long-term cumulative use (>4.4 years) of PPIs from mid- to late life was associated with a 33.0% increased risk of dementia in late life (HR, 1.3). Of note, current use in late life or shorter-term use in midlife was not associated with a higher risk of dementia in late life.
- This study suggests that long-term cumulative PPI use increases the risk of dementia. Further studies exploring the pathways between PPI use and the development of dementia are needed.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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 (1987-89) through 2017. PPI use was assessed via visual medication inventory at clinic Visits 1 (1987-89) to 5 (2011-13) and reported annually in study phone calls (2006-2011). The present study uses ARIC Visit 5 as baseline, since this was the first visit in which PPI use was common. PPI use was examined two ways: current use at Visit 5 and duration of use prior to Visit 5 (Visit 1 to 2011, exposure categories: 0 days, 1 day - 2.8yrs, 2.8-4.4yrs, >4.4yrs). The outcome was incident dementia after visit 5. Cox Proportional Hazard models were used, adjusted for demographics, co-morbid 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. Minimum cumulative PPI use was 112 days and maximum use was 20.3 years. There were 585 cases of incident dementia over median follow up time. 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 prior to 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 amounts 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 use of prescribed PPIs for > 4.4 years by individuals ages 45 years and older is associated with a higher incidence of newly diagnosed dementia.
Additional Info
Disclosure statements are available on the authors' profiles:
Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study
Neurology 2023 Aug 09;[EPub Ahead of Print], C Northuis, E Bell, P Lutsey, KM George, RF Gottesman, TH Mosley, EA Whitsel, K LakshminarayanFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
PPIs and dementia risk
Previous findings from studies on proton pump inhibitor (PPI) use and the association with the risk of dementia have been mixed. However, the concerns for the association of prolonged PPI use with the risk of cardiovascular disease, kidney disease, and stroke are building. These studies are showing consistent findings that the short-term use of PPIs is safe, but the long-term risk is accumulative. The longer one is on a PPI, the higher the risk.
The Atherosclerotic Risk in Communities (ARIC) study followed 5712 individuals for a median follow up of 5.5 years. After controlling for confounding variables, there was a 33% higher risk of dementia for individuals on PPIs for more than 4.4 years. There was no association between PPI use and dementia for individuals on these medications for less than the aforementioned duration.
Since PPIs completely shut down the acid pump, but H2 blockers only partially block the production acid, H2 blockers appear to be safer in the long term. This study did not show an association of dementia with H2 blockers.
The researchers may have underestimated the number of people on PPIs since they only counted those who were prescribed PPIs and did not account for those who obtained the medicine over the counter.
What is the mechanism of potential harm?
We do not know, but our body makes acid for a reason and simply turning it off will likely have consequences.
Acid helps with lysis. Lysosomes lyse by using a proton pump to create an acidic environment. This defense mechanism helps keep the lining of our blood vessels clean and reduces amyloid plaque.
PPIs inhibit key enzymes that help break down amyloid and that also convert nitrates to nitric oxide. This may result in more amyloid and more atherosclerosis.
Acid helps absorb nutrients. PPIs reduce the absorption of several nutrients but the one that may influence memory the most is B12. This risk is exacerbated if the patient is also on metformin.
Acid diversifies the microbiome. Being on a PPI reduces the diversity of the microbiome resulting in a dysbiosis commonly seen in individuals with dementia.