Abstract: Proton-pump inhibitors (PPIs) are first line therapy for most gastroesophageal acid-related disorders. They include reflux disorders, Helicobacter pylori infections, Zollinger-Ellison syndrome, and gastroesophageal malignancies. In clinical practice, PPIs have largely replaced histamine-2 receptor antagonists (H2RAs) due to their superior efficacy and are currently widely prescribed and sold worldwide. (Kantor et al., 2015). Since the PPIs are, in addition, freely available without prescription in the United States, there has been a growing concern over proton-pump inhibitor prolonged use and serious side effects such as Alzheimer’s disease (AD) type dementia. A few large scale studies have shown an increased risk of the AD type and non-AD type dementia with PPI use, while others have questioned this association (Novotny et al., 2018; Khan et al., 2020). Aside from the memory impairment related adverse events, PPI use has been reported to be associated with neuropathies in a few case reports (Rajabally and Jacob, 2005). We investigated these associations by analyzing of postmarketing adverse event (AE) reports for patients on PPI (n = 42,537) and H2RA (n = 8309) monotherapy in United States Food and Drug Administration Adverse Event Reporting System datasets. Initially, every report where a PPI or an H2RA was used were selected into the antacid cohort. The data set was further split into PPI and H2RA arms. Reports where a PPI or an H2RA was the only medication used were selected into their respective cohorts, excluding all concurrent medications and comorbidities. Adverse event report rates were analyzed via odds ratio analysis and 95% confidence intervals. We found a significantly increased risk of memory impairment, including both AD- and non- AD type dementia conditions, in PPI-treated patients (odds ratio 3.28, 95% confidence interval [2.31, 4.67]) (Makunts et al., 2019a). Additionally, we found that virtually every neurologic disease state related adverse event had a significantly higher reporting frequency and increased risk in the PPI monotherapy cohort: hearing impairment (11.64 [5.20, 26.11]), visual impairment (1.85 [1.44, 2.37]), neurological/ neuropathic impairment (8.68 [3.86, 19.49], seizure related adverse events (1.54 [1.06, 2.24]), and migraines (2.19 [1.29, 3.72]) (Makunts et al., 2019a). To the best of our knowledge this was the first large scale study to confirm the previously observed associations of PPI use with a wide range of neurological AEs involving both central and peripheral nervous systems (CNS and PNS).