Proton pump inhibitors (PPIs) are a class of drugs used for the treatment of acid-related diseases by inhibiting gastric acid secretion. Although PPIs are considered safe and clinically beneficial in the short term, mounting evidence raises safety concerns about the long-term use of PPIs. Alzheimer’s disease (AD) is the most common form and cause of dementia and one of the biggest public health challenges among neurodegenerative diseases in the elderly, with no effective treatment to date. In recent years, there have been conflicting studies in patients receiving long-term PPIs regarding the risk of dementia, and in particular, AD. Some studies showed a strong positive relationship between PPIs and their impact on dementia and AD. We performed an in-depth review and analysis of existing studies and performed some docking to investigate the interaction between PPIs and dementia, AD-associated proteins, enzymes, and receptors. This study aims to provide possible new insights about the long-term safety of PPI employment and eventual cognitive impairment leading to dementia and later AD.