Background <p>Clinical studies about the association between long-term PPI use and dementia have been inconsistent, with systematic reviews and meta-analyses (SR/MA) reaching disparate conclusions.</p> Aims <p>This umbrella review of SR/MA—or overview of reviews—attempts to clarify the current understanding of any possible association linking PPI use to dementia.</p> Methods <p>We searched EMBASE, MEDLINE, Cochrane Database of Systematic Reviews (CDSR), and ISI Web of Science for fully published SR/MA in English up to June 2024 using controlled vocabulary and text words [(1) proton pump inhibitor and (2) dementia (dementia and mild cognitive impairment, Alzheimer disease)]. SR/MA methodological overall confidence was scored using the AMSTAR-2 tool.</p> Results <p>Eleven SR/MA published (May 2016–June 2024) described 21 studies (one randomized trial). The number of studies in these SR/MA ranged from 4 to 14. Six of the included SR/MA reported data on Alzheimer’s disease. Only one of the high-overall confidence SR/MA significantly associated PPI use with dementia. None of the six SR/MA investigating PPI use and Alzheimer’s disease showed a significant association. Significant associations with dementia in subgroup analyses were found in SR/MA for older patients (one of three SR/MA) (Hazard ratio (HR) = 1.39 (1.17;1.65)), long-term PPI use (one of four SR/MA) (HR = 1.28 (1.12; 1.46)), short-term PPI use (one of four SR/MA) (Risk ratio (RR) = 1.62 (1.40–1.86)), when only considering higher quality studies (one of one SR/MA) (RR = 1.54 (1.12; 2.13)), among European populations (one of three SR/MA) (HR = 1.46 (1.23–1.73)), and cohort studies (two of four SR/MA) (RR = 1.36 (1.19; 1.55)), (RR = 1.44 (1.36; 1.52)).</p> Conclusion <p>Most SRs/MAs suggest no link between PPI use and dementia. Given the low certainty of existing evidence, a true causal relationship appears unlikely. Keywords: PPIs; Dementia; Alzheimer’s disease; Cognitive impairment.</p>