Objectives: To examine the risk associated with the use of proton pump inhibitors (PPIs) of conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer's disease (AD). Design: Observational, longitudinal study. Setting: Tertiary academic Alzheimer's Disease Centers funded by the National Institute on Aging. Participants: Research volunteers aged 50 and older with two to six annual visits; 884 were taking PPIs at every visit, 1,925 took PPIs intermittently, and 7,677 never reported taking PPIs. All had baseline normal cognition or MCI. Measurements: Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition to MCI or dementia or annual conversion of baseline MCI to dementia, controlling for demographic characteristics, vascular comorbidities, mood, and use of anticholinergics and histamine-2 receptor antagonists. Results: Continuous (always vs never) PPI use was associated with lower risk of decline in cognitive function (hazard ratio (HR) = 0.78, 95% confidence interval (CI) =0.66–0.93, P =.005) and lower risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.69–0.98, P =.03). Intermittent use was also associated with lower risk of decline in cognitive function (HR = 0.84, 95% CI = 0.76–0.93, P =.001) and risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.74–0.91, P =.001). This lower risk was found for persons with normal cognition or MCI. Conclusion: Proton pump inhibitors were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and lack of dispensing data. Prospective studies are needed to confirm these results to guide empirically based clinical treatment recommendations.