Table 2. Observational studies.
| 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. 14 , 2015 | Gomm et al. 15 , 2016 | Goldstein et al. 35 , 2017 | Gray et al. 28 , 2017 | Lochhead et al. 27 , 2017 | Hwang et al. 30 , 2018 | Park et al. 31 , 2018 | Wod et al. 29 , 2018 | Huang et al. 37 , 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. 36 , 2019 | Welu et al. 32 , 2019 | Chen et al. 33 , 2020 | Cooksey et al. 34 , 2020 | Torres-Bondia et al. 16 , 2020 | Wu et a.l 38 , 2020 | Ma et al. 42 , 2020 | Booker et al. 41 , 2016 | Taipale et al. 40 , 2017 | Imfeld et al. 39 , 2018 | |
Abbreviations: LE: level of evidence; ACD: all-cause dementia; HR: hazard ratio; AD: Alzheimer's dementia; CI: confidence interval; p: p-value; MCI: Mild Cognitive Impairment; TSDDS: Total standardized daily doses; aSR: adjusted sequence ratio; PPI: Proton pump inhibitors; IRR: incidence rate ratio; aHR: adjusted hazard ratio; aOR; adjusted odds ratio; RR: relative risk; nAD: non-Alzheimer dementia.