Understanding the Complex Relationship Between Long-Term PPI Use and Dementia

Proton pump inhibitors (PPIs) have long been a mainstay in the treatment of various gastrointestinal conditions, including gastroesophageal reflux disease (GERD) and peptic ulcers.

However, recent research has turned the spotlight on potential links between long-term PPI use and an increased risk of dementia.

A community-based cohort study has delved into this connection, revealing intriguing insights that shed light on the multifaceted relationship between these medications and cognitive health.

The study, centered on a community-based cohort, focused on individuals who had engaged in long-term cumulative PPI use exceeding 4.4 years from mid-to-late life. The findings unveiled a modestly elevated risk of dementia in late life for participants with this prolonged PPI exposure, in comparison to those who had not used PPIs.

However, shorter-term use during midlife and current use in late life did not show an increased risk of dementia. This nuance underscores the significance of considering the duration and timing of PPI use when evaluating its potential effects on cognitive health.

The realm of research into PPIs and dementia has been marked by mixed results from previous cohort studies. This study’s findings align with the results of two heterogeneous meta-analyses, both of which reported no substantial association between time-varying PPI use and dementia risk.

These meta-analyses considered a similar follow-up period as the current study (ranging from 1.5 to 8.4 years) and often classified participants into PPI users and nonusers. The agreement between the results of this cohort study and the meta-analyses underscores the complexity of the relationship and the need for comprehensive investigations.

However, one aspect that sets this study apart is its consideration of the long latency period of dementia. A Finnish nationwide nested case-control study introduced the concept of a 3-year lag window, revealing no immediate association between PPI use and Alzheimer’s disease risk.

Similarly, a US cohort study focused on a 10-year period of daily PPI dose dispensed, finding no significant connection to dementia risk. In contrast, the current study’s data indicated that cumulative long-term use of over 4.4 years was significantly associated with an increased risk of developing dementia.

To comprehend the potential mechanisms underlying the PPI-dementia relationship, researchers have proposed two plausible pathways: vitamin B12 deficiency and impaired amyloid metabolism.

Previous studies have noted a significant link between PPI use and lower levels of Vitamin B12, which in turn have been associated with cognitive decline.

While participant B12 levels were not available in the current dataset, adjusting for baseline B12 use did not alter the association between PPI use and dementia. Additionally, experimental studies in mice have suggested that PPI use could contribute to increased levels of β-amyloid in the brain, a hallmark of Alzheimer’s disease.

Moreover, researchers have explored potential connections between PPIs and dementia via the microbiota-gut-brain axis. PPI use has been linked to alterations in the gut microbiome, which have also been observed in patients with Alzheimer’s disease. The pathways linking gut dysbiosis and cognitive decline include neuro-inflammation, oxidative stress, and the triggering of amyloid-beta aggregation. This underscores the intricate interplay between various physiological systems and cognitive health.

Another consideration in the realm of PPI use is its role in eradicating H. pylori infection. H. pylori, a gastric pathogen, has been associated with dementia, although the data remains observational. Quadruple therapy involving PPIs for H. pylori eradication typically lasts for 14 days, indicating short-term PPI use. However, the current study highlights a connection between cumulative long-term PPI use and dementia risk, emphasizing the complexity of the relationship.

This study’s strength lies in its comprehensive approach. It includes physician-adjudicated dementia cases, providing a robust basis for analysis. The study’s ability to capture PPI use since FDA approval in 1989 adds historical context, while the inclusion of a racially diverse cohort enriches its applicability. Adjusting for the APOE4 genotype further enhances the study’s rigor.

Nevertheless, several limitations are acknowledged. Despite meticulous adjustment for confounders, residual confounding remains a concern. The last-observation-carried-forward method may have led to misestimation of PPI exposure, and over-the-counter availability could have impacted the control group. The sample’s US-centric nature may limit generalizability, and the exclusion of participants with missing covariate data introduces potential bias.

In conclusion, the intricate relationship between long-term PPI use and dementia remains a subject of intensive investigation. This community-based cohort study offers insights into the potential cognitive risks of prolonged PPI exposure, considering cumulative use duration and timing.

The study underscores the importance of further research to unravel the complex mechanisms linking PPIs to cognitive health and the necessity of addressing potential mediators in long-term PPI use and dementia risk. As the medical community strives to comprehensively understand this relationship, healthcare providers and patients alike should remain vigilant and informed about the potential cognitive impact of extended PPI use.

reference link :https://n.neurology.org/content/early/2023/08/09/WNL.0000000000207747