Purpose of Review <p>The widespread and increasing use of proton pump inhibitors (PPIs), particularly among middle-aged and older adults, has raised concerns regarding potential long-term neurological effects. Given the rising global burden of dementia, this review aims to critically evaluate the current preclinical and clinical evidence examining the association between chronic PPI use and cognitive impairment, including dementia.</p> Recent Findings <p>Experimental studies suggest that PPIs can cross the blood–brain barrier (BBB) and may influence neurobiological pathways implicated in dementia, including amyloid-β (Aβ) metabolism, tau pathology, neuroinflammation, synaptic dysfunction, and oxidative stress. Clinical and observational studies have reported heterogeneous findings, with some suggesting an increased risk of cognitive decline or dementia, particularly in older or genetically susceptible populations, while others report no significant association after adjustment for confounders. Emerging evidence highlights indirect mechanisms linking long-term PPI use to cognitive dysfunction, such as vitamin B12 deficiency, gut microbiota dysbiosis with disruption of the gut–brain axis, and impaired calcium homeostasis. However, most available data are observational and susceptible to confounding by indication, polypharmacy, and reverse causation.</p> Summary <p>Current evidence linking PPI use to cognitive decline and dementia remains inconclusive. While biologically plausible mechanisms exist, clinical findings are inconsistent and do not establish causality. These uncertainties underscore the importance of cautious, evidence-based PPI prescribing, regular medication review, and appropriate monitoring in long-term users, particularly older adults. Well-designed longitudinal, mechanistic, and interventional studies are needed to clarify potential neurocognitive risks and identify vulnerable populations.</p>